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Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugsA one-year randomized placebo-controlled study.

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ARTHRITIS & RHEUMATISM
Vol. 54, No. 9, September 2006, pp 2807–2816
DOI 10.1002/art.22070
© 2006, American College of Rheumatology
Safety of the Selective Costimulation Modulator Abatacept in
Rheumatoid Arthritis Patients Receiving Background Biologic
and Nonbiologic Disease-Modifying Antirheumatic Drugs
A One-Year Randomized, Placebo-Controlled Study
M. Weinblatt,1 B. Combe,2 A. Covucci,3 R. Aranda,3 J. C. Becker,3 and E. Keystone4
patients in either group experienced a severe or very
severe infection. The incidence of neoplasms was 3.5% in
both groups. When evaluated according to background
therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a
biologic agent (22.3%) than in the other subgroups
(11.7–12.5%).
Conclusion. Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes. However, abatacept in combination with
biologic background therapies was associated with an
increase in the rate of serious adverse events. Therefore,
abatacept is not recommended for use in combination
with biologic therapy.
Objective. To assess the safety of abatacept, a
selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving
>1 traditional nonbiologic and/or biologic diseasemodifying antirheumatic drugs (DMARDs) approved
for the treatment of RA for at least 3 months prior to
entry into the study.
Methods. This was a 1-year, multicenter, randomized, double-blind, placebo-controlled trial. Patients
were randomized 2:1 to receive abatacept at a fixed dose
approximating 10 mg/kg by weight range, or placebo.
Results. The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%,
respectively), serious adverse events (13% and 12%,
respectively), and discontinuations due to adverse
events (5% and 4%, respectively). Five patients (0.5%) in
the abatacept group and 4 patients (0.8%) in the placebo
group died during the study. Serious infections were
more frequent in the abatacept group than in the
placebo group (2.9% versus 1.9%). Fewer than 4% of
T cells play a fundamental role in the upstream
initiation and perpetuation of the pathologic immune
response in rheumatoid arthritis (RA), resulting in
downstream inflammation and destruction (1). Following antigen recognition, T cells require a costimulatory
signal for full activation, with one of the best characterized pathways being the engagement of CD80/86 on
antigen-presenting cells with CD28 on T cells (2). Following the normal immune response, endogenous
CTLA-4 down-regulates CD28-mediated T cell activation by binding to CD80/86 with higher avidity than
CD28 (3). The important role of T cells in the immune
response in RA makes T cell activation a rational
therapeutic target for treatment of this disease.
Abatacept is a fully human soluble fusion protein
that consists of the extracellular domain of human
CTLA-4 linked to the modified Fc portion of human
IgG1. Abatacept is the first in a new class of agents for
Supported by Bristol-Myers Squibb.
1
M. Weinblatt, MD: Brigham and Women’s Hospital, Boston,
Massachusetts; 2B. Combe, MD: Hopital Lapeyronie, Montpellier,
3
France; A. Covucci, MSc, R. Aranda, MD, J. C. Becker, MD:
Bristol-Myers Squibb, Princeton, New Jersey; 4E. Keystone, MD:
Mount Sinai Hospital, Toronto, Ontario, Canada.
Drs. Weinblatt and Keystone have received consultancies
and/or honoraria (less than $10,000) from Bristol-Myers Squibb,
Abbott, Amgen, Wyeth, Centocor, and Genentech. Dr. Combe has
received consultancies and/or honoraria (less than $10,000) from
Briston-Myers Squibb, Abbott, and Sanofi. Drs. Aranda and Becker
own stock and/or stock options in Bristol-Myers Squibb.
Address correspondence and reprint requests to M. Weinblatt, MD, Rheumatology and Immunology, Brigham and Women’s
Hospital, 75 Francis Street, Boston, MA 02115. E-mail: mweinblatt@
partners.org.
Submitted for publication February 15, 2006; accepted in
revised form June 9, 2006.
2807
2808
WEINBLATT ET AL
the treatment of RA that selectively modulates the
CD80/86:CD28 costimulatory signal required for full T
cell activation. Abatacept, a selective costimulation
modulator, has previously demonstrated efficacy, safety,
and tolerability in combination with methotrexate
(MTX) in clinical trials of patients in whom the response
to MTX was inadequate (4,5). Furthermore, a trial of
abatacept on a background of disease-modifying antirheumatic drugs (DMARDs) in patients with an inadequate response to anti–tumor necrosis factor (anti-TNF)
therapy recently demonstrated a significant efficacy benefit of abatacept in this unique RA patient population (6).
The Abatacept Study of Safety in Use with Other
RA Therapies (ASSURE trial) was designed to assess
the safety of abatacept compared with placebo in patients with active RA during 1 year of abatacept treatment added to a background of treatment with ⱖ1 of the
traditional nonbiologic and/or biologic DMARDs currently approved for the treatment of RA. This trial was
designed to assess the safety of abatacept in patients
with RA who would be encountered in clinical practice.
PATIENTS AND METHODS
Role of the funding source. Bristol-Myers Squibb was
involved in the design of the study (conducted between December 17, 2002 and June 21, 2004) and collection and analysis
of the data.
Patients. The study group comprised men and women
at least 18 years of age who met the 1987 American College of
Rheumatology (ACR; formerly, the American Rheumatism
Association) criteria for the diagnosis of RA (7) and the 1991
ACR criteria for RA functional classes I, II, III, or IV (8).
Patients had to have active disease despite receiving background DMARDs and/or biologic therapy, warranting additional therapy at the discretion of the investigator. To qualify
for this study, the average score for the patient’s global
assessment of disease activity, as assessed by visual analog
scale (VAS) measurements obtained at the time of screening
and randomization (day 1), was required to be ⱖ20 mm.
Patients were required to have been receiving ⱖ1 biologic
and/or nonbiologic DMARD approved for RA for at least 3
months, and at a stable dose for at least 28 days prior to day 1
of the trial. Patients with stable medical conditions such as
congestive heart failure (CHF), asthma, chronic obstructive
pulmonary disease (COPD), and diabetes mellitus were included.
Patients were excluded if they had unstable or uncontrolled renal, endocrine, hepatic, hematologic, gastrointestinal,
pulmonary, cardiac, or neurologic diseases, or any autoimmune disorder other than RA as the main diagnosis. Other
exclusion criteria were active or chronic recurrent bacterial
infections unless treated and resolved, active herpes zoster
infection within the previous 2 months, hepatitis B or hepatitis
C virus infection, and active or latent tuberculosis (as assessed
via chest radiography and tuberculin testing) unless appropriately treated. Pregnant or nursing women were also excluded.
Study protocol. This was a 1-year, multinational, multicenter, randomized, double-blind, 2-arm, parallel-dosing
trial. Eligible patients were randomized 2:1 to receive abatacept (at a fixed dose approximating 10 mg/kg) or placebo by
intravenous infusion. The fixed dosing regimen was based on
the following body weight range: 500 mg for patients with a
body weight ⬍60 kg, 750 mg for patients with a body weight of
60–100 kg, and 1 gram for patients with a body weight ⬎100 kg.
Patients completing the double-blind phase of the study were
allowed to enter a long-term, open-label extension phase
during which all patients received a fixed dose of abatacept
approximating 10 mg/kg. The study was carried out in accordance with the ethical principles of the Declaration of Helsinki
and was approved by institutional review boards. All patients
gave informed consent before undergoing any screening procedure.
Treatment administration. Medication (abatacept or
placebo) was administered via a 30-minute intravenous infusion on days 1, 15, and 29, and every 4 weeks thereafter, for
a total of 14 doses.
Concomitant medications. All patients were required
to continue to receive their background RA therapies (biologic
DMARDs, nonbiologic DMARDs, or a combination of both)
at study entry. For the purposes of the study, approved biologic and nonbiologic DMARDs included the following: MTX,
hydroxychloroquine, leflunomide, gold, azathioprine, anakinra,
etanercept, infliximab, and adalimumab. Stable, low-dose oral
corticosteroids (10 mg/day or less) and/or stable doses of
nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin (acetylsalicylic acid [ASA]), were allowed. During the
first 3 months of the trial, adjustments in background RA
therapy (nonbiologic DMARDs, biologic DMARDs, or corticosteroids) were not allowed except for decreases in dose due
to toxicity. Analgesics that did not contain ASA or NSAIDs
were permitted to be administered to patients who were
experiencing pain that was not adequately controlled by baseline and study medications. Additional analgesics or NSAIDs
that were not part of background RA therapy were not
permitted within the 12 hours preceding the patient’s global
assessment of disease activity on days 1, 85, 169, and 253. After
the first 3 months (days 86–365), adjustments in background
RA therapy were permitted, including the withdrawal or
addition of nonbiologic DMARDs, biologic DMARDs, or
corticosteroids. Patients were permitted to adjust the dosage of
existing DMARDs or add additional DMARDs; however, dose
modification of the study medication was not permitted.
Therapies that were prohibited during the study included
mycophenolate mofetil, cyclosporine, other calcineurin inhibitors, D-penicillamine, cyclophosphamide, and apheresis (immunoadsorption columns).
Safety. Overall assessments. The primary objective of
the ASSURE trial was to evaluate the safety of abatacept in
patients with active RA, including those with comorbid conditions, during 1 year of abatacept treatment added to a background of ⱖ1 of the traditional biologic and/or nonbiologic
DMARDs approved for RA. All patients who received at least
1 dose of study medication were evaluated for the occurrence
of adverse events (AEs), serious adverse events (SAEs), discontinuations due to AEs, death, clinically significant changes
THE ASSURE TRIAL
in vital signs, physical examination abnormalities, and clinical
laboratory test abnormalities.
Adverse and serious adverse events. An AE was defined
as any new or worsening illness, sign, symptom, or clinically
significant laboratory test abnormality noted by the investigator or patient during the course of the study, regardless of
causality. Intensity was rated by the investigator on a scale of
1 (mild) to 4 (very severe). An SAE was defined as an AE that
met any of the following criteria: was fatal, was lifethreatening, resulted in hospitalization, resulted in persistent
or significant disability or incapacity, was a malignancy, was a
congenital anomaly or birth defect, resulted in an overdose or
drug dependency, or was deemed an important medical event,
as determined by the investigator. The severity of AEs (including infections) was assessed by the investigator.
Prespecified infusion events. Prespecified infusion
events represented a collection of AE terms (mostly representative of hypersensitivity reaction) selected from the Medical
Dictionary for Regulatory Activities codes for a possible
association with an infusion reaction. Acute infusional events
were described as AEs occurring within 1 hour of the start of
infusion. Periinfusional events were described as AEs occurring within 24 hours of the start of infusion.
Prespecified autoimmune events. Autoimmune disorders of interest (including systemic lupus erythematosus, multiple sclerosis, and psoriasis) were identified according to a
predefined list of terms and definitions.
Clinical outcome measures. Three patient-reported
components of the ACR core data set (9) were exploratory
secondary efficacy objectives in this study. These measures
have been shown to discriminate the efficacy of study treatments compared with that of placebo as effectively as composite ACR response measures (10). Physical function was assessed using the Disability Index of the Health Assessment
Questionnaire (HAQ) (11). Patient’s global assessment of
disease activity, patient’s global assessment of pain, and physician’s global assessment of disease activity were all assessed
using a 100-mm VAS.
Statistical analysis. Data were assessed for all patients
treated with either abatacept or placebo in order to ascertain
the safety and patient- and physician-reported benefit of
abatacept in the overall population (all patients, regardless of
background therapy) of this study. Furthermore, data from
each treatment group were assessed according to background
therapy (nonbiologic DMARDs versus biologic DMARDs) to
determine whether differences in the effects of abatacept
between these patient populations would be evident.
Safety analyses were based on a data set containing all
available assessments from all patients who received at least 1
infusion of study medication (treated patients). The study was
powered to detect AEs occurring at a rate of 0.2%. No formal
tests were planned to compare AE incidence rates between
treatment groups. Exploratory efficacy analyses were performed on the 4 clinical outcome measures. For each of these
measures, descriptive statistics, including the median percent
improvement from baseline, the mean percent improvement
from baseline, and the mean change from baseline, were
provided for all time points. A post hoc analysis was used to
assess each efficacy outcome according to background therapy
(nonbiologic DMARDs versus biologic DMARDs).
2809
Figure 1. Patient disposition to 1 year.
RESULTS
Patient disposition and baseline characteristics.
Of the 1,456 patients randomized, 1,441 received at least
1 infusion of study medication. A total of 1,231 patients
(87.2% of those assigned to abatacept and 82.0% of
those assigned to placebo) completed 1 year of doubleblind treatment (Figure 1).
The majority of patients were white women. The
mean ⫾ SD age for the overall study population was
52.3 ⫾ 11.8 years, and the mean duration of RA was
approximately 9.7 ⫾ 8.9 years. Disease duration was
typically longer in patients receiving biologic DMARDs
than in those receiving nonbiologic DMARDs (11.3
years versus 9.5 years). The treatment groups were
similar with respect to demographic characteristics and
most baseline disease characteristics, with the exception
of the C-reactive protein level, which was slightly higher
in the subgroup receiving nonbiologic background therapy (Table 1).
Among all patients overall (both the abatacept
and placebo groups), the prevalence of comorbidities
was as follows: for diabetes mellitus (type 1 or type 2),
6–7%; for type 2 diabetes mellitus, 6%; for asthma, 6%;
for COPD, 4%; and for CHF, 1–2%.
2810
WEINBLATT ET AL
Table 1. Baseline demographic and clinical characteristics of the patients, according to background
therapy*
Nonbiologic background
therapy
Biologic background
therapy
Parameter
Abatacept
(n ⫽ 856)
Placebo
(n ⫽ 418)
Abatacept
(n ⫽ 103)
Placebo
(n ⫽ 64)
Age, years
Female sex, no. (%)
White race, no. (%)
Disease duration, years
Pain, 100-mm VAS
Physical function, HAQ DI score
Patient’s global assessment, 100-mm VAS
Physician’s global assessment, 100-mm VAS
C-reactive protein, mg/dl
52.2 ⫾ 11.8
711 (83.1)
718 (83.9)
9.5 ⫾ 8.7
61.1 ⫾ 20.4
1.5 ⫾ 0.6
60.6 ⫾ 19.7
57.8 ⫾ 17.4
1.9 ⫾ 2.4
52.0 ⫾ 12.1
350 (83.7)
348 (83.3)
9.5 ⫾ 9.1
61.3 ⫾ 20.8
1.5 ⫾ 0.7
61.3 ⫾ 20.1
58.3 ⫾ 17.5
2.1 ⫾ 2.6
54.6 ⫾ 11.2
78 (75.7)
100 (97.1)
11.3 ⫾ 8.9
62.2 ⫾ 20.3
1.5 ⫾ 0.6
60.3 ⫾ 19.8
57.4 ⫾ 17.8
1.4 ⫾ 1.9
52.8 ⫾ 11.4
48 (75.0)
59 (92.2)
11.3 ⫾ 9.6
61.5 ⫾ 20.0
1.6 ⫾ 0.6
58.7 ⫾ 17.2
57.6 ⫾ 17.6
1.5 ⫾ 1.9
* Except where indicated otherwise, values are the mean ⫾ SD. The nonbiologic background therapy
subgroup was defined as all patients who received a nonbiologic agent at any time during the study or up
to 56 days following discontinuation. The biologic background therapy subgroup was defined as all
patients who received a biologic agent at any time during the study or up to 56 days following
discontinuation. VAS ⫽ visual analog scale; HAQ DI ⫽ Disability Index of the Health Assessment
Questionnaire.
Background therapy. Results are presented according to background RA therapies (nonbiologic versus
biologic DMARDs). The biologic subgroup was defined
as all patients who received biologic DMARDs at any
point during the course of the study or up to 56 days
following discontinuation of study medication. At the
time of randomization, the majority of patients were
receiving 1 background DMARD (69% of the abatacept
group and 65% of the placebo group). Smaller numbers
of patients were receiving 2 DMARDs (24% and 29%,
respectively) or 3 DMARDs (6% and 5%, respectively),
while less than 1% of patients in either group were
receiving 4 or more background DMARDs.
Concomitant RA medications that were being
received by patients in the nonbiologic and biologic
subgroups are summarized in Table 2. Of the 959
patients assigned to receive abatacept, 855 (89.2%)
received nonbiologic RA therapy (abatacept plus nonbiologic subgroup) and 103 (10.7%) received background
biologic RA therapy (abatacept plus biologic subgroup)
during the trial. Corresponding numbers of patients
assigned to the placebo group who received background
nonbiologic or biologic therapy were 417 (86.5%; placebo plus nonbiologic subgroup) and 64 (13.3%; placebo
plus biologic subgroup).
The most frequently used nonbiologic DMARD
was MTX (in the nonbiologic subgroup, 80.7% of patients receiving abatacept and 80.4% of those receiving
placebo; in the biologic subgroup, 56.3% of patients
receiving abatacept and 56.3% of those receiving placebo). In the biologic subgroup, 87.4% of patients
assigned to abatacept and 87.5% of those assigned to
placebo were receiving anti-TNF therapy. The most
commonly used biologic therapy was etanercept (64.1%
and 65.6% of the abatacept and placebo groups, respectively).
After month 3, when changes in background
DMARDs were permitted, fewer abatacept-treated patients than placebo-treated patients received additional
nonbiologic DMARDs (4.3% and 7.7%, respectively),
while a similar proportion of patients from the abatacept
and placebo groups discontinued additional nonbiologic
DMARDs (5.6% and 5.2%, respectively). In terms of
background biologic therapy, 0.9% of patients in the
abatacept group and 1.9% of those in the placebo group
received additional therapy. The proportions of
abatacept-treated patients and placebo-treated patients
who discontinued additional biologic therapy were 1.1%
and 0.6%, respectively.
Safety. Overall adverse events and serious adverse
events. Overall, the abatacept and placebo groups were
similar in terms of the incidence of AEs (90% and 87%,
respectively), SAEs (13% and 12%, respectively), and
severe or very severe AEs (16% and 15%, respectively).
Discontinuations due to AEs were infrequent in both
treatment groups, occurring in 5% and 4% of the
abatacept and placebo groups, respectively. Five patients
(0.5%) in the overall abatacept group and 4 patients
(0.8%) in the overall placebo group died during the
1-year, double-blind treatment period. Four of the
deaths occurring in the abatacept group (hypertensive
heart disease 2 days following the first infusion, coronary
THE ASSURE TRIAL
2811
Table 2. Concomitant rheumatoid arthritis medication received by the patients, according to background therapy*
Nonbiologic background
therapy
Biologic background
therapy
Therapy
Abatacept
(n ⫽ 856)
Placebo
(n ⫽ 418)
Abatacept
(n ⫽ 103)
Placebo
(n ⫽ 64)
Nonbiologic DMARDs
Methotrexate
Hydroxychloroquine/chloroquine
Sulfasalazine
Leflunomide
Gold
Azathioprine
Biologic DMARDs
Anti–tumor necrosis factor therapy
Etanercept
Infliximab
Adalimumab
Anakinra
Corticosteroids (oral and/or injectable)
855 (99.9)
691 (80.7)
194 (22.7)
137 (16.0)
106 (12.4)
24 (2.8)
23 (2.7)
0
0
0
0
0
0
613 (71.6)
417 (99.8)
336 (80.4)
123 (29.4)
72 (17.2)
59 (14.1)
10 (2.4)
17 (4.1)
0
0
0
0
0
0
308 (73.7)
81 (78.6)
58 (56.3)
15 (14.6)
11 (10.7)
15 (14.6)
1 (1.0)
3 (2.9)
103 (100)
90 (87.4)
66 (64.1)
20 (19.4)
11 (10.7)
13 (12.6)
77 (74.8)
52 (81.3)
36 (56.3)
7 (10.9)
4 (6.3)
12 (18.8)
1 (1.6)
3 (4.7)
64 (100)
56 (87.5)
42 (65.6)
5 (7.8)
10 (15.6)
10 (15.6)
51 (79.7)
* Values are the number (%). The nonbiologic background therapy subgroup was defined as all patients
who received a nonbiologic agent at any time during the study or up to 56 days following discontinuation.
The biologic background therapy subgroup was defined as all patients who received a biologic agent at any
time during the study or up to 56 days following discontinuation. Two patients (1 in the abatacept group
and 1 in the placebo group) were not receiving disease-modifying antirheumatic drugs (DMARDs) at any
time during the study, or for 56 days following discontinuation, and these patients were protocol violators.
atherosclerosis and acute ischemic cardiopathy 13 days
following the twelfth infusion, central atherosclerosis
and significantly advanced coronary atherosclerosis with
focal stenosis 7 days following the thirteenth infusion,
and cardiac arrest 29 days following the twelfth infusion)
and 3 of the deaths in the placebo group (CHF 55 days
following the seventh infusion, cardiopulmonary arrest
37 days following the fourteenth infusion, and cardiac
arrest 28 days following the fourteenth infusion) were
deemed either unlikely to be related or unlikely to be
unrelated to study medication. For the remaining abatacept patient, the cause of death was unknown, because
no autopsy was performed. The remaining death in the
placebo group was the result of Pneumocystis carinii
pneumonia, which was deemed possibly related to the
investigational drug by the study investigator, who was
blinded to therapy at the time of assessment. This
patient had been receiving background RA therapy with
MTX, gold salts, prednisone, and chloroquine. A summary of AEs according to treatment subgroup and
background therapy is shown in Table 3.
Nonbiologic background therapy. Total AEs in
the subgroup receiving nonbiologic background therapy
occurred at similar rates in the abatacept plus nonbiologic subgroup and the placebo plus nonbiologic subgroup (89.7% and 86.1%, respectively), as did discon-
tinuations due to AEs (5.0% and 4.3%, respectively).
The most common AE was headache (20.3% of patients
in the abatacept plus nonbiologic subgroup versus 13.9%
of those in the placebo plus nonbiologic subgroup).
Total SAEs occurred at similar rates in the abatacept
plus nonbiologic subgroup and the placebo plus nonbiologic subgroup (11.7% and 12.2%, respectively), while
discontinuations due to SAEs were more frequent in the
abatacept plus nonbiologic subgroup (2.1% and 1.2%,
respectively). In a subpopulation of patients receiving
background leflunomide (106 patients in the abatacept
group and 59 patients in the placebo group), total SAEs
occurred more frequently in those receiving abatacept
than in those receiving placebo (23.6% versus 15.3%).
The most common events were musculoskeletal and
connective tissue disorders (8.5% versus 5.1%) and
infections/infestations (7.5% versus 5.1%). There was no
trend in the particular type of AE associated with the
use of abatacept plus background leflunomide. In contrast, the percentage of SAEs in the subpopulations of
patients receiving abatacept on a background of MTX
and those receiving placebo on a background of MTX
was similar (10.6% versus 11.0%), while SAEs occurred
less frequently in patients receiving abatacept on a
background of sulfasalazine than in those receiving
2812
WEINBLATT ET AL
Table 3. Summary of adverse events, serious adverse events, and serious infections, according to
background therapy*
Nonbiologic background
therapy
Event
Deaths
Total adverse events
Related adverse events
Discontinuations due to adverse
events
Total serious adverse events
Related serious adverse events
Discontinuations due to serious
adverse events
Serious infections
Total neoplasms
Most common neoplasms†
Uterine leiomyoma
Fibroadenoma of breast
Basal cell carcinoma
Most common adverse events‡
Infections
Gastrointestinal disorders
Nervous system disorders
Musculoskeletal and connective
tissue disorders
Serious infections
Respiratory
Dermatologic
Urinary
Gastrointestinal
Gynecologic
Opportunistic
Pneumocystis pneumoniae
Candidiasis
Other
Biologic background
therapy
Abatacept
(n ⫽ 856)
Placebo
(n ⫽ 418)
Abatacept
(n ⫽ 103)
Placebo
(n ⫽ 64)
5 (0.6)
768 (89.7)
473 (55.3)
43 (5.0)
4 (1.0)
360 (86.1)
203 (48.6)
18 (4.3)
0
98 (95.1)
61 (59.2)
9 (8.7)
0
57 (89.1)
36 (56.3)
2 (3.1)
100 (11.7)
18 (2.1)
18 (2.1)
51 (12.2)
10 (2.4)
5 (1.2)
23 (22.3)
5 (4.9)
5 (4.9)
8 (12.5)
3 (4.7)
2 (3.1)
22 (2.6)
27 (3.2)
7 (1.7)
16 (3.8)
6 (5.8)
7 (6.8)
1 (1.6)
1 (1.6)
4 (0.5)
4 (0.5)
3 (0.4)
1 (0.2)
0
3 (0.7)
0
0
2 (1.9)
0
0
0
470 (54.9)
350 (40.9)
304 (35.5)
229 (26.8)
224 (53.6)
148 (35.4)
121 (28.9)
112 (26.8)
67 (65.0)
40 (38.8)
37 (35.9)
28 (27.2)
37 (57.8)
20 (31.3)
23 (35.9)
20 (31.3)
9 (1.1)
5 (0.6)
4 (0.5)
2 (0.2)
0
0
0
0
3 (0.4)
4 (1.0)
1 (0.2)
1 (0.2)
1 (0.2)
1 (0.2)
2 (0.5)
1 (0.2)
1 (0.2)
0
3 (2.9)
0
2 (1.9)
1 (1.0)
0
0
0
0
1 (1.0)
1 (1.6)
0
0
0
0
0
0
0
0
* Values are the number (%). The nonbiologic background therapy subgroup was defined as all patients
who received a nonbiologic agent at any time during the study or up to 56 days following discontinuation.
The biologic background therapy subgroup was defined as all patients who received a biologic agent at any
time during the study or up to 56 days following discontinuation.
† Occurring in ⬎0.2% of patients receiving abatacept plus nonbiologic background therapy.
‡ Occurring in ⬎25% of patients in all groups.
placebo on a background of sulfasalazine (10.9% versus
12.5%).
Biologic background therapy. Among patients
receiving biologic background therapy, total AEs were
more frequent in those in the abatacept subgroup compared with the placebo subgroup (95.1% versus 89.1%),
as were discontinuations due to AEs (8.7% versus
3.1%). In the subpopulation of patients receiving biologic background therapy, the most common AE was
headache, and this was reported more frequently in
those receiving abatacept than in those receiving placebo (20.4% versus 15.6%). Total SAEs were more
frequent in patients receiving abatacept than in those
receiving placebo (22.3% versus 12.5%), as were discon-
tinuations due to SAEs (4.9% versus 3.1%). In the small
subgroup of patients receiving background anakinra (13
patients assigned to receive abatacept and 10 patients
assigned to the placebo group), the frequencies of total
SAEs were 15.4% and 20.0%, respectively.
Infections. Overall incidence of infections. Infections were the most common adverse events reported in
both treatment groups (for abatacept, 56.0%; for placebo, 54.1%). The most frequent infections (upper
respiratory tract infection and nasopharyngitis) occurred
at similar rates in the abatacept and placebo groups
(15% for both groups and 10% for both groups, respectively). Fewer than 4% of patients in either treatment
group had a severe or very severe infection; however,
THE ASSURE TRIAL
serious infections (i.e., those that were fatal or lifethreatening, those that resulted in hospitalization, and
those that resulted in persistent or significant disability
or incapacity) occurred more frequently in the abatacept
group (2.9% versus 1.9% in the placebo group). For the
majority of patients, the serious infections were treatable and did not result in discontinuation of treatment.
All of the serious infections in the abatacept group were
bacterial in origin. In patients treated with abatacept
during the year-long study period, no infection attributed to an opportunistic microorganism was seen, no
cases of tuberculosis were observed, and no fatalities due
to infection occurred.
Nonbiologic background therapy versus biologic
background therapy. Serious infections occurred more
frequently in the subpopulation of patients receiving
abatacept plus nonbiologic therapy than in those receiving placebo plus nonbiologic therapy (2.6% versus 1.7%)
and in patients receiving abatacept plus biologic therapy
(5.8% versus 1.6% of patients receiving placebo plus
biologic therapy). These infections consisted of single
events of cellulitis, intestinal abscess, infective bursitis,
and pyelonephritis. In the small subgroup of patients
receiving background anakinra, serious infections occurred more frequently with abatacept than with placebo
(7.7% versus 0%).
Malignancies. Overall incidence of malignancies.
The overall incidence of neoplasms (benign, malignant,
and unspecified) was 3.5% in both the abatacept group
and the placebo group. Neoplasms reported as SAEs
occurred in 1.5% of abatacept-treated patients and in
1.0% of placebo-treated patients. Skin carcinomas (primarily basal cell or squamous cell) were reported most
commonly. Breast cancer was reported in 1 patient
(0.1%) in the abatacept group and in 2 patients (0.4%)
in the placebo group. Three lung cancers were reported
in the abatacept group (0.3%) compared with none in
the placebo group; 2 of the 3 patients with lung cancer
had a history of smoking, and 2 patients had short
duration (29 and 100 days) of therapy prior to the
diagnosis of malignancy. One patient with lung cancer
had an abnormal baseline radiograph, and this patient
also had a synchronous renal malignancy. There were no
reports of lymphoma.
Nonbiologic background therapy versus biologic
background therapy. The incidence of neoplasms (benign, malignant, and unspecified) was 7% in the group
of patients receiving abatacept plus biologic therapy
compared with 2% in the group receiving placebo plus
biologic therapy. Within the subgroup receiving abatacept plus biologic therapy, there were 3 reports of
2813
malignant cancers (2 basal cell carcinomas and 1 squamous cell carcinoma). None of these 3 malignancies was
rated as severe or very severe or resulted in study
discontinuation, and each one was considered either
unrelated or unlikely to be related to the study drug.
Autoimmune events. Prespecified autoimmune
events were reported at a similar rate in the 2 treatment
groups (3.3% and 3.1% in the abatacept and placebo
groups, respectively). Reported events in both treatment
groups included keratoconjunctivitis sicca and vasculitis.
There were no reports of multiple sclerosis or any other
demyelinating disorders.
Infusion-related adverse events. The incidences of
acute infusion-related (within 1 hour of the start of
infusion) and periinfusional (within 24 hours of the start
of infusion) events were similar in the abatacept group
(acute, 10.0%; periinfusional, 24.3%) and the placebo
group (acute, 7.1%; periinfusional, 20.3%). The most
frequent of these events were headache and dizziness.
Few patients in the abatacept group had a severe acute
(0.7%) or periinfusional (1.5%) event. Two patients in
each treatment group experienced hypersensitivity reactions within 1 hour of infusion. Overall, prespecified
acute infusional or periinfusional events resulted in
discontinuation in only a small number of patients (0.6%
of patients receiving abatacept and 0.2% of those receiving placebo).
Patients with comorbid conditions. The numbers
of patients with CHF and asthma were too small to
permit conclusions to be drawn. However, the overall
frequencies of SAEs and discontinuation due to AEs
among patients receiving abatacept and those receiving
placebo were generally comparable.
Patients with COPD. Among patients with COPD,
adverse events were reported in 97.3% of those receiving
abatacept (n ⫽ 37) and 88.2% of those receiving placebo
(n ⫽ 17). More AEs involving the respiratory system
occurred in patients with COPD treated with abatacept
than in those treated with placebo (43.2% versus
23.5%), the majority of which were of mild-to-moderate
intensity. The most common respiratory AEs among
abatacept-treated patients with COPD (occurring with a
frequency ⬎5%) were cough, rhonchi, exacerbation of
chronic obstructive airway disease, chronic obstructive
airway disease, dyspnea, and nasal congestion. Infections
were the most common organ system class of events
reported as AEs among patients with COPD and occurred with a similar frequency in both the abatacept
and placebo groups (59.5% and 58.8%, respectively). In
the abatacept group, the most common infection-related
AEs (occurring in ⱖ5% of patients) were upper respi-
2814
ratory tract infection, bronchitis, sinusitis, influenza,
lower respiratory tract infection, herpes zoster infection,
and respiratory tract infection. The pattern and types of
infections were similar to those observed in abatacepttreated patients without COPD.
Among patients with COPD, more SAEs were
reported in those treated with abatacept than in those
receiving placebo (27% versus 5.9%). Serious AEs reported for abatacept-treated patients with COPD included intestinal ischemia, colon adenoma, COPD, exacerbated COPD, squamous cell carcinoma of the skin,
RA (2 cases), bronchitis, basal cell carcinoma (2 cases),
cellulitis, cataract, and eye surgery. These events were
more common in patients treated with abatacept than in
those treated with placebo. Serious AEs of a respiratory
nature were more commonly reported by patients receiving abatacept (10.8%; 1 exacerbation of COPD, 1
worsening of COPD, 1 bronchitis, 1 pneumonia) than by
those receiving placebo (0%). Among abatacept-treated
patients with COPD who had SAEs, no death occurred.
Patients with diabetes mellitus. Among patients
with diabetes mellitus, adverse events were reported by
93.8% of those in the abatacept group (n ⫽ 65) and
90.3% of those in the placebo group (n ⫽ 31). Infections
were the most common organ system class of events
reported as AEs among patients with diabetes mellitus
and occurred at a modestly lower frequency in the
abatacept group compared with the placebo group
(50.8% versus 58.1%). More abatacept-treated patients
with diabetes mellitus reported SAEs than did placebotreated patients with diabetes mellitus (21.5% versus
12.9%), and this was driven by increases in SAEs in the
Figure 2. Patient- and physician-reported outcomes at 1 year. VAS ⫽
visual analog scale; HAQ DI ⫽ Disability Index of the Health
Assessment Questionnaire. ⴱ ⫽ Sixteen patients were excluded from
the efficacy analysis due to compliance issues at one center.
WEINBLATT ET AL
Figure 3. Disability Index of the Health Assessment Questionnaire
(HAQ DI) at 1 year, according to background therapy. ⴱ ⫽ Sixteen
patients were excluded from the efficacy analysis due to compliance
issues at one center.
organ system classes of musculoskeletal disorders and
injury.
Clinical outcome measures. Patient- and
physician-reported outcomes. In the overall study population (all patients, regardless of background therapy),
mean changes from baseline in patient- and physicianreported disease outcomes (patient’s assessment of pain,
patient’s global assessment, and physician’s global assessment) at 1 year were significantly better for
abatacept-treated patients (⫺26.3, ⫺27.2, and ⫺33.5,
respectively) compared with placebo-treated patients
(⫺16.4, ⫺17.4, and ⫺23.6, respectively) (P ⬍ 0.001 for
all comparisons). In a post hoc analysis, improvements
from baseline in all patient- and physician-reported
outcomes were greatest in the group receiving abatacept
plus nonbiologic therapy (Figure 2).
Physical function. At 1 year, the mean change
from baseline in physical function (Disability Index of
the HAQ) was greater in patients treated with abatacept
compared with those treated with placebo (⫺0.46 versus
⫺0.25; P ⬍ 0.001). Similarly, in a further post hoc
analysis, improvements from baseline in physical function were seen in both abatacept treatment subgroups,
with the differences between the abatacept and placebo
groups being greatest in patients receiving nonbiologic
background DMARDs (Figure 3).
DISCUSSION
Several randomized studies have demonstrated
the efficacy of abatacept in patients with active RA. In a
THE ASSURE TRIAL
phase IIb trial (5), therapy with abatacept plus MTX in
patients with an inadequate response to MTX provided
significant improvements in terms of the ACR 20%
(ACR20), ACR50, and ACR70 criteria (9) compared
with placebo at 1 year (for ACR20, 63% versus 36%; for
ACR50, 42% versus 20%; for ACR70, 21% versus 8%).
A phase III trial in a similar patient population demonstrated similar benefit with abatacept versus placebo (for
ACR20, 73% versus 40%; for ACR50, 48% versus 18%;
for ACR70, 29% versus 6%) (12), while a further phase
III trial of 6 months duration in patients with a current
or previous inadequate response to anti-TNF therapy
also demonstrated significant benefit with abatacept in
this unique patient population (for ACR20, 50% versus
19.5%; for ACR50, 20% versus 4%; for ACR70, 10%
versus 2%) (6). In all trials, abatacept provided significant improvement in patients’ physical function and
quality of life (5,6,12).
The primary end point of the ASSURE trial was
to evaluate the safety of abatacept compared with
placebo when added to a background of approved
synthetic DMARDs and/or biologic DMARDs over the
course of 1 year, in a blinded, randomized study. This
study revealed overall similarity between the abatacept
and placebo groups in their respective frequency of AEs,
SAEs, and severe or very severe AEs; furthermore,
discontinuations due to AEs were infrequent in both
treatment groups. The overall frequency of neoplasms
was similar in the abatacept and placebo groups. Lung
cancer was the most frequently reported solid malignancy in this study (n ⫽ 3). A causal relationship to
abatacept therapy is considered less likely in this group,
considering that 2 of these patients had a very short
duration of treatment, and 1 patient had an abnormal radiograph at baseline. However, the data are too
limited to permit a definitive conclusion, and longerterm observation will be required. There were no reports of lymphoma, tuberculosis (for which patients
were screened prior to treatment), or demyelinating
disorders.
When assessed according to background therapy,
the rates of AEs and SAEs were similar in the subgroup
receiving abatacept plus nonbiologic background therapy and the subgroup receiving placebo plus nonbiologic
background therapy. However, AEs, SAEs, and discontinuations were all most frequent when abatacept was
combined with background biologic therapy. It should
be noted that the proportion of patients who experienced an SAE was greater among those receiving leflunomide plus abatacept than in those receiving leflunomide plus placebo; however, there was no trend for
2815
any specific organ system class or type of SAE, and the
sample size of this group was relatively small. In the
subgroup of patients with COPD, respiratory system–
related AEs and SAEs were reported in a greater
proportion of patients in the abatacept group compared
with the placebo group, although the overall number of
patients with COPD in this study was small. Nonetheless, the findings in this study indicate that abatacept
should be used with caution and with close monitoring of
respiratory status in patients with RA and COPD.
The ASSURE trial involved 1 year of observation; however, greater clinical experience over longer
periods of observation and in larger populations of
patients with comorbidities is required to validate these
findings. An important finding in this study was the
number of serious infections observed when abatacept
was combined with other biologic therapies. This confirms the findings of a smaller phase II study in which
abatacept (2 mg/kg) in combination with the anti-TNF
agent etanercept was associated with a higher rate of
serious infections than was etanercept plus placebo after
1 year of double-blind therapy (Weinblatt M, et al:
unpublished observations). In contrast, across clinical
trials of abatacept in combination with nonbiologic
therapy, the reported incidence of serious infections was
lower than that reported here for patients receiving
abatacept in combination with biologic background therapy. Genovese et al (6) reported that among patients
who experienced an inadequate response to anti-TNF
therapy, at 6 months the number of serious infections
was comparable in patients receiving abatacept plus
DMARDs and in those receiving placebo plus
DMARDs (2.3% for both). More recently, among a
group of patients with an inadequate response to MTX,
serious infections in the abatacept group were of a
similar magnitude to those in patients with an inadequate response to anti-TNF therapy (3.9% and 2.3%,
respectively, for patients receiving abatacept plus MTX
and those receiving placebo plus MTX) (12).
Although efficacy was not a primary end point of
the ASSURE trial, and as such this study was not
designed to prospectively assess the efficacy of abatacept
between subgroups, the benefit seen with abatacept in
terms of physical function and physician- and patientreported pain and global assessment tended to be less in
patients receiving background biologic therapy compared with those receiving background nonbiologic therapy. A post hoc analysis was used to assess each efficacy
outcome according to background therapy; although
post hoc analyses may not be deemed optimal, the lack
of clinical benefit seen here in the group of patients
2816
WEINBLATT ET AL
receiving abatacept plus biologic therapy is consistent
with that seen in the phase II study of abatacept in
combination with etanercept.
Coupled with the less favorable safety profile
seen in patients receiving abatacept on a background of
biologic therapy, these findings are consistent with the
lack of added benefit and increased rate of infection
seen when other biologic agents were used in combination (e.g., etanercept plus anakinra) (13). In that study,
patients receiving etanercept plus anakinra had a higher
frequency of serious infection compared with those
receiving etanercept alone (3.7–7.4% versus 0%), and
the number of ACR responders was lower (13). Based
on the results of the ASSURE trial and the phase II
study evaluating the concomitant use of abatacept and
etanercept, a favorable benefit-to-risk ratio with abatacept in combination with other biologic therapies is not
apparent; therefore, use of abatacept in combination
with biologic therapies is not advised.
The safety and tolerability of abatacept in the
ASSURE trial was favorable when abatacept was given
in combination with nonbiologic DMARDs; the number
of good clinical outcomes was also greater in this
subgroup over the course of 1 year. Selective costimulation modulation with abatacept is an effective therapy
for RA, with an acceptable safety profile when used in
combination with a variety of background nonbiologic
DMARDs.
ACKNOWLEDGMENTS
We would like to thank all of the physicians, nurses,
study coordinators, and patients for their important contributions to the ASSURE trial. We would also like to thank Claire
Smart, PhD, Medicus International, for her editorial assistance.
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receiving, abatacept, years, patients, selective, biological, modifying, disease, costimulation, drugs, antirheumatic, nonbiological, one, stud, controller, arthritis, randomized, background, modulators, safety, placebo, rheumatoid
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