## Center for Biologics Evaluation and Research

**Office of Therapeutics Research and Review**

**Division of Clinical Trial Design and Analysis**

> **Immunology and Infectious Diseases Branch**

**HFM-582**

CLINICAL REVIEW

Abbott, Biologic Licensing Application

STN 125057

Adalimumab - for use in the treatment of rheumatoid arthritis

Scheldon Kress, M.D.

###### TABLE OF CONTENTS

I. Introduction

A.
Background..........................................................................................................3

B. Adalimumab Clinical Development
Program..................................................................4

C. Regulatory
History..................................................................................................5

II\. Study DE 009

A. Clincal Trial
Design...............................................................................................10

B. Study
conduct......................................................................................................11

C. Efficacy
Analysis..........................................................................................
....12

III\. Study DE 011

A. Clincal Trial
Design...............................................................................................14

B. Study
Conduct......................................................................................................16

C. Efficacy Analyses

1\. Efficacy
Endpoints.................................................................................\..........22

2\. Efficacy
Analysis............................................................................................23

3\. Summary of Efficacy
Data..............................................................................\...29

IV\. Study DE 019

A. Clincal Trial
Design...............................................................................................29

B. Study
Conduct................................................................................................\......32

C. Efficacy
Analyses..........................................................................................\.......37

1\. Primary Efficacy
Endpoints................................................................................37

a\. ACR20 at Week
24....................................................................................38

b\. Modified Total Sharp Score (radiographic progression) at week
52...........................43

c\. Disability Index
(HAQ)..............................................................................54

2\. Secondary Efficacy
Endpoints............................................................................55

3\. Summary of Efficacy
Data..............................................................................\...57

**V**. Study DE031

A. Clincal Trial
Design..............................................................................................58

B. Study
Conduct.....................................................................................................61

C. Safety
Analyses................................................................................................\...65

D. Efficacy
Analysis................................................................................................76

E. Summary of
Analyses...........................................................................................79

VI\. Integrated Safety Analysis

A. Safety
Database...................................................................................................79

B. Treatment -Emergent Adverse
Events..........................................................................82

C. Other Adverse
Events.............................................................................................85

D. Deaths and Comparable Mortality
Rates.......................................................................86

E. Serious Adverse
Events...........................................................................................90

F. Malignancies and Comparative Expected Incidence
Rates..................................................92

G. Serious Infections
................................................................................................97

H. Tuberculosis and Other Opportunistic
Infections.........................................................\...102

I. ANA and Anti-dsDNA
.......................................................................................\...104

J. Lupus-Like
Syndromes....................................................................................\......104

K. Immunologic
Reactions.........................................................................................105

L. Demyelinating
Disease.......................................................................................\...105

M. Adverse Events Leading to Withdrawal, Temporary Interruption, and
Reduction of Study Drug\....106

N. Laboratory
Abnormalities......................................................................................
.111

O.
Immunogenicity..................................................................................................114

P. Impact of Dose on
Safety.......................................................................................117

Q. Impact of Dose Intyerruption on
Safety......................................................................118

R. Impact of Age on
Safety........................................................................................120

S. Impact of Concomitant Methotrexate on
Safety.............................................................122

VII\. Financial
Disclosure........................................................................\...123

VIII.Overall Summary of Safety and
Efficacy.........................................\.......123

I. Introduction

##### A. Background

Rheumatoid arthritis (RA) is a chronic, inflammatory disorder of the
joints with a female predominance. A prevalence of 1% has been reported
in the adult population. The disease is characterized by a progressive
inflammatory synovitis manifested by polyarticular joint swelling and
tenderness. The synovitis results in erosion of articular cartilage and
marginal bone with subsequent joint destruction. RA produces substantial
morbidity and increased mortality. Studies of natural history of the
disease indicate that within 2 years of diagnosis, patients usually
experience moderate disability; after 10 years 30% are severely
disabled. Assessment of the efficacy of any treatment for RA entails
clinical, physical function, and laboratory measures i.e., a composite
measure of disease activity improvement.

The FDA issued a Guidance Document for evaluating new treatments of RA
in February 1999 (Clinical Development Programs for Drugs, Devices, and
Biological Products Intended for the Treatment of Rheumatoid Arthritis).
The guidance document recognized claims for efficacy based on
improvement in signs and symptoms and a group of enhanced claims. For
demonstration of efficacy, the standards set forth requires improvement
in signs and symptoms of RA in a clinical trial of at least six months
duration based on validated composite endpoints or indices of signs and
symptoms such as the American College of Rheumatology (ACR) criteria for
20% improvement (the ACR20). Demonstration of effectiveness in
inhibition of progression of structural damage, assessed via a method
like the modified Sharp score, requires a clinical trial of at least
twelve months duration. Since RA is a chronic disease, demonstration of
durability of efficacy is also expected. For products with the potential
to elicit antibody formation, assessment for durability is particularly
important, since antibodies that develop over time may block
effectiveness.

The enhanced claims recognized in the RA Guidance Document include the
ability to achieve: a major clinical response, defined as an ACR70 for
six consecutive months; a complete clinical response, defined using ACR
criteria for remission and no radiographic progression for six
consecutive months while receiving ongoing drug therapy; and a
remission, defined as a remission by ACR criteria and no radiographic
progression for six consecutive months while off all anti-rheumatic
therapy. To encourage long-term trials, the claim of improvement in
physical function requires a validated measure of improvement in
disability such as the HAQ (Health Assessment Questionnaire), Arthritis
Impact Measure Scale (AIMS), as well as evidence of improvement or, at
least, no worsening in a measure of health related-quality of life such
as the SF-36 for two to five years. The E1A ICH guidance document
recommends that for chronically administered products, the minimum
safety data-base requires at least 300-600 patients treated with the
recommended dose for at least six months, at least 100 patients treated
for at least twelve months, and a total of 1000 to 1500 patients treated
overall. However, longer term data may be required if late developing
AEs are observed or if AEs are observed that increase in severity or
frequency over time. In addition, more data may be required if there are
concerns based on preclinical toxicity testing, pharmacology, or
inferences from similar agents.

Current drug therapy for RA includes non-steroidal anti-inflammatory
drugs (NSAIDs) and corticosteroids to provide symptomatic relief. Some
disease-modifying antirheumatic drugs (DMARDs) have been demonstrated to
inhinit disease progression; some patients fail to achieve an adequate
or sustained response to therapy due to lack of efficacy or toxicity.

The recent introduction of new classes of therapeutic agents has
contributed to major advances in the treatment of RA. The first TNF-α
blocking agents, infliximab and etanercept, were approved for
improvement in signs and symptoms of RA. In addition, the TNF-α blockers
have demonstrated inhibition of progression of structural joint damage
among patients with RA. More recently anakinra, the first IL-1 blocking
agent, has been approved for improvement in signs and symptoms of RA.
All three of these agents are generally well tolerated, but have been
associated with uncommon serious adverse events, primarily serious
infections.

These newer novel biological agents inhibit the action of cytokines,
hormone-like proteins that mediate communication between cells, and play
critical roles in normal biologic processes, such as cell growth,
inflammation, and immunity. Both tumor necrosis factor (TNF-α) and
interleukin-1 (IL-1) have been implicated in the progression of
inflammatory synovitis and articular matrix degradation. Being foreign
proteins, these biologic agents are potentially immunogenic, and studies
have been carried out to determine whether antibodies over time diminish
clinical activity and increase the incidence of adverse events.
Treatment with infliximab has been associated with antibody formation,
particularly in patients receiving treatment without concurrent MTX.
Antibody-positive patients were more likely to experience infusion
reactions.

B.  **Adalimumab Clinical Development Program**

Adalimumab is a human-derived recombinant IgG1 monoclonal antibody
engineered by gene technology. Adalimumab binds to TNF-α but not TNF-β
and has a half-life of approximately 2 weeks. This antibody has been
extensively studied *in vitro* as well as *in vivo* and no major
toxicity was observed in animal studies. This submission presents data
from three phase III clinical trials and assesses the efficacy and
safety of adalimumab in the treatment of RA. Since TNF-α is an important
cytokine affecting inflammation and immunity, patients were closely
monitored and data were submitted for possible adverse events (AE),
especially serious infections, malignancies, and immunogenic potential.
In addition, the possible role of human antibodies to adalimumab on
efficacy and safety was evaluated.

The adalimumab clinical development program includes 23 studies, 17 of
which were conducted in RA patients, four of these studies (DE009,
DE011, DE019, and DE031) represent controlled trials assessing the
effectiveness of adalimumab, and four clinical pharmacology studies
(DE015, DE024C, DE024J, and DE029) performed in healthy volunteers.
Figure 1 depicts the overall group of studies in the adalimumab clinical
development program. Table 1 lists the studies that are discussed and
provides summary information on studies providing evidence of efficacy.
Patients treated concomitantly with MTX participated in trials conducted
almost entirely in North America. Patients not concomitantly treated
with MTX participated in trials conducted almost entirely in
Europe/Australia/Canada.

The proposed indication for Adalimumab is for "reducing signs and
symptoms and inhibiting the progression of structural damage in adult
patients with moderately to severely active RA who have had an
inadequate response to one or more DMARDs.

**Adalimumab can be used alone or in combination with MTX or other
DMARDs."**

Safety data were provided in the BLA for approximately 2000 patients
treated with adalimumab through August 31, 2001 for a median of 12
months, and were updated through August 31, 2002 for a median of 24
months.

**C. Regulatory History**

Shortly after the IND (#7627) for the study of D2E7 (adalimumab) became
effective April 16, 1998, the sponsor submitted adverse event reports of
cases of serious infections and deaths occurring in studies in Europe
that had occurred prior to the time of the submission but were not
provided to the FDA in the IND submission. The nine serious infectious
adverse events (AEs) reported while patients were receiving adalimumab
included: septic arthritis, post-operative wound infection, interstitial
pneumonitis, miliary tuberculosis with pleural effusion, lymphatic
tuberculosis, streptococcal pneumonia with empyema, gluteal abscess,
forearm abscess, and multiple antibiotic resistant pneumonia combined
with flaring of pre-existing SLE (systemic lupus erythematosus). By
delaying the submission of these AEs to the Agency, the FDA was
prevented from adequately assessing the risks to the subjects in the
proposed clinical investigation. Based on the occurrence of these
serious infections in Europe, all D2E7 clinical trials were placed on
clinical hold on June 19, 1998, until these safety concerns could be
adequately addressed.

Several explanations were provided by the sponsor including: the larger
number of serious infections observed occurred among sicker patients,
tuberculosis was more common in Europe, some subjects originally
suspected of having infections had chronic infections at baseline or had
no infections, and some of the subjects would have been excluded from US
trials. In Study DE010 (adalimumab with MTX), which was similar to the
proposed US Study in inclusion criteria, the incidence of serious
infections was much lower. After intensive review of the explanations
submitted by the sponsor, the sponsor was requested to initiate new
precautions. On this basis, the clinical hold was removed on August 11,
1998 and the proposed study was allowed to proceed. In order to proceed,
investigators were to be informed of the possibility of sepsis, to
encourage early recognition and appropriate therapy and include
information stating a potential increased risk of infections in the
Informed Consent.

In December 1999, the Agency noted that eight cases of tuberculosis had
been submitted as expedited safety reports. These tuberculosis cases
occurred among 477 patients (1.7% incidence) administered adalimumab in
Europe. The Agency requested the sponsor to provide additional
information on these cases and determine whether actions could be taken
to avoid further cases. Typically, the cases occurred among
heavily--treated patients 58-70 years of age with long-standing RA, 4-6
months after initiating D2E7 therapy, and it was determined in
retrospect that 80% of the patients had a baseline chest x-ray highly
suspicious for prior tuberculosis. No cases of tuberculosis had been
seen in US trials.

The sponsor agreed to proposed trial stopping rules, the appointment of
a Data Safety Monitoring Board to review unblinded safety data,
initiation of screening measures for pre-existing tuberculosis,
prophylactic tuberculosis treatment when appropriate prior to
administration of D2E7, and the early reporting of serious and
unexpected SAEs to the Agency.

![](media/image1.png){width="8.791666666666666in"
height="4.927083333333333in"}

> Figure 1: Study groupings for Integrated Summary of Effectiveness Data

Table 1 : Studies Providing Substantial Evidence of Efficacy

![](media/image2.png){width="8.75in" height="2.875in"}

![](media/image3.png){width="8.59375in" height="3.1145833333333335in"}

## II. Study DE009 - Dose-Ranging Trial

**A. Clinical Trial Design -- DE009**

Study DE009 is a phase II 24 week multicenter double blind randomized
placebo-controlled dose-ranging trial to evaluate therapeutic effects,
safety, tolerability, and immunogenicity of adalimumab administered
subcutaneously every other week with concomitant MTX among patients with
a confirmed diagnosis of rheumatoid arthritis. Patients were required to
have insufficient efficacy or significant toxicity with MTX at weekly
doses 12.5 to 25 mg. The dose of MTX had to be stable for at least 4
weeks before a patient could be screened. Patients receiving 10 to 12.5
mg MTX with documented intolerance to higher doses could also be
enrolled. The dose of MTX was to remain constant during the 24-week
study period. Patients must have been receiving MTX for at least 6
months before screening.

The study objective is to investigate whether every other week
subcutaneous (sc) treatment with 20, 40, or 80 mg adalimumab for up to
24 weeks results in a significantly higher ACR20 response rate compared
to treatment with placebo over the same treatment

period.

The primary efficacy endpoint of this study was the American College of
Rheumatology 20% (ACR20) response as reported at Week 24. A patient was
given the classification of "responder" to ACR20 if all of the following
criteria were met:

-   A []{.underline}20% improvement in TJC (tender joint count).

-   A []{.underline}20% improvement in SJC (swollen joint count).

-   A []{.underline}20% improvement in three of the five remaining
    ACR core set measures:

> 1\. Patient assessment of pain.
>
> 2\. Patient global assessment of disease activity.
>
> 3\. Physician global assessment of disease activity.
>
> 4\. Patient self-assessed disability (disability index of the Health
>
> Assessment Questionnaire \[HAQ\]).
>
> 5\. Acute phase reactant (C-reactive protein \[CRP\]).

Patients who did not meet all of the above criteria, as well as those
who withdrew from the study prior to Week 24 (i.e., prior to the end of
the placebo-controlled period) were classified as "non-responders." Each
patient who withdrew from the study prior to Week 24 due to an AE was
counted as a non-responder.

Secondary efficacy endpoints included ACR50 and ACR70, time to response
for ACR20, ACR50, ACR70, ACR-N \[defined as the least percent
improvement (from baseline) in number of 1) tender and 2) swollen
joints, and 3) the median percent improvement in a) pain assessment, b)
physician and c) patient global assessment, d) physical function, and e)
acute phase reactants, and incorporates all disease activity measures of
the ACR response\], AUC (area under the curve) for numeric ACR response
\[defined as the product of numeric ACR multiplied by the time a patient
is at that level of improvement, which dynamically measures improvement
over time (area under the curve of numeric ACR over time)\], tender
joint count (TJC) -- an assessment of 68 joints or regions done by
pressure or joint manipulation on physical examination, swollen joint
count (SJC) -- An assessment of 66 joints done by physical examination,
assessment of pain, Patient Global Assessment of disease activity, Heath
Status (Disability Index of the HAQ), Functional Assessment of Chronic
Illness Therapy (FACIT), and serologic evaluations, which included
cytokine levels (IL-1, IL-6, and TNF), rheumatoid factor (RF), and
markers for cartilage destruction (proMMP-1 and proMMP-3).

**B. Study Conduct -- DE009**

A total of 336 patients were screened, 271 patients were randomized, and
253 completed

the study (at least 16 weeks of treatment). Planned enrollment was for
268 patients. Due to the fact that one of the investigators was in the
process of being debarred, the eleven (11) patients enrolled at his site
were removed from the efficacy analysis. As a result, the efficacy
analysis consisted of 260 patients and the demographic and safety
analyses include 271 patients. A total of 209 patients received
adalimumab and 62 patients received placebo. Figure 2 summarizes the
planned conduct of the study.

> ![](media/image4.png){width="3.8333333333333335in"
> height="4.364583333333333in"}
>
> Figure 2 : Design of Study DE009

The Statistical Analysis Plan (SAP) consisted of an efficacy analysis on
the intent-to-treat (ITT) population of all patients who were
randomized, received at least one injection of double-blind study drug,
and for whom any assessment of efficacy under double-blind conditions
was available. The primary efficacy analysis consisted of a comparison
of the change in ACR20 response rates at Week 24 compared to placebo on
the intent-to-treat population. The ACR20 response rates of the three
adalimumab groups were compared with the placebo group rates. Dunnett's
method, with an overall alpha level of 0.05, was used to adjust for the
multiple comparisons of each active treatment group with a single
control. Thus, statistical significance required demonstration of a
proportionally greater level of efficacy for additional comparisons.

C.  **Efficacy Analysis**

The primary efficacy assessment was a comparison of the ACR20 response
rates (using CRP as the acute phase reactant) between the individual
adalimumab treatment groups (20, 40, and 80 mg subcutaneous every 2
weeks) and placebo at Week 24 utilizing Dunnett's method to adjust for
the multiple comparisons. After 24 weeks of treatment, each adalimumab
treatment group (20, 40, and 80 mg) was statistically significantly
superior (p ≤ 0.05) to placebo for the ACR20 response. The response at
Week 24 was comparable between the 40 mg (67%) and 80 mg (66%) doses,
was slightly lower for the 20 mg (48%) dose, and was significantly lower
for the placebo (13%) (Table 2).

Table 2 : Study DE009: ACR20 response: Number (%) of patients responding
over time by randomized treatment group (full analysis set, excluding
Site #7)

+-------------------+----------+------------+-----------+-------------+
|                   | # Ad     |            |           | # Placebo   |
|                   | alimumab |            |           |             |
+-------------------+----------+------------+-----------+-------------+
|                   | **20     | **40 mg**  | **80 mg** |             |
|                   | mg**     |            |           |             |
+-------------------+----------+------------+-----------+-------------+
| # Time point      | (N=67)   | (N=63)     | (N=70)    | (N=60)      |
+-------------------+----------+------------+-----------+-------------+
| **Week 24         | 32       | **42       | 46        | **8 (13%)** |
| (observed)**      | (48%)^a^ | (67%)^a^** | (66%)^a^  |             |
+-------------------+----------+------------+-----------+-------------+
| **LOCF Week 24**  | 34 (51%) | **42 (67%) | 46 (66%)  | **8 (13%)** |
|                   | ^a^      | ^a^**      | ^a^       |             |
+-------------------+----------+------------+-----------+-------------+
| ^a^ Statistically |          |            |           |             |
| significantly     |          |            |           |             |
| different from    |          |            |           |             |
| placebo (p≤0.05). |          |            |           |             |
+-------------------+----------+------------+-----------+-------------+

As a secondary analysis provided for in the protocol, the last
observation was also carried forward (LOCF) to Week 24 for patients who
withdrew from the study for reasons other than AEs or those who went
into open-label treatment prior to Week 24. Week 24 LOCF data
demonstrated similar values between adalimumab and placebo relative to
observed values (Table 2). In comparison, fewer placebo-treated patients
showed improvement at Week 24.

Adalimumab-treated patients achieved higher ACR50, and ACR70 responses
than placebo-treated patients (Table 3).

Table 3 : Study DE009 : ACR50 and ACR70 Responses By Randomized
Treatment Group

+-------------------+----------+------------+-----------+-------------+
|                   | # Ad     |            |           | # Placebo   |
|                   | alimumab |            |           |             |
+-------------------+----------+------------+-----------+-------------+
|                   | **20     | **40 mg**  | **80 mg** |             |
|                   | mg**     |            |           |             |
+-------------------+----------+------------+-----------+-------------+
| # Time point      | (N=67)   | (N=63)     | (N=70)    | (N=60)      |
+-------------------+----------+------------+-----------+-------------+
| # ACR50           |          |            |           |             |
+-------------------+----------+------------+-----------+-------------+
| Week 24           | 22 (33%) | **34       | 29 (41%)  | 4 (7%)      |
| (observed)        |          | (54%)**    |           |             |
+-------------------+----------+------------+-----------+-------------+
| LOCF Week 24      | 22 (32%) | **34       | 29 (41%)  | 4 (7%)      |
|                   |          | (54%)**    |           |             |
+-------------------+----------+------------+-----------+-------------+
| ###### ACR70      |          |            |           |             |
+-------------------+----------+------------+-----------+-------------+
| Week 24           | 7 (10%)  | **15       | 13 (19%)  | 2 (3%)      |
| (observed)        |          | (24%)**    |           |             |
+-------------------+----------+------------+-----------+-------------+
| LOCF Week 24      | 7 (10%)  | **15       | 13 (19%)  | 2 (3%)      |
|                   |          | (24%)**    |           |             |
+-------------------+----------+------------+-----------+-------------+
| ^\*^              |          |            |           |             |
| Statistically     |          |            |           |             |
| significantly     |          |            |           |             |
| different from    |          |            |           |             |
| placebo (p≤0.05). |          |            |           |             |
+-------------------+----------+------------+-----------+-------------+

Adalimumab-treated patients achieved ACR20 responses faster and more
often than placebo-treated patients. ACR20 responses are displayed
graphically for the full analysis set of patients in Figure 3. Overall,
the adalimumab treatment groups had a higher response at each time point
compared to placebo. There is separation between adalimumab- and
placebo-treated patients as early as Week 1, and the separation
continues through Week 24.

![](media/image5.png){width="6.197916666666667in"
height="3.9895833333333335in"}

#  

> Figure 3 : Study DE009: Responder Rates to ACR20

**III. Study DE011**

A.  **Clinical Trial Design**

Clinical trial DE011 is a Phase III 26 week adalimumab monotherapy trial
to evaluate efficacy, safety, and immunogenicity of two doses (20 and 40
mg) and two dosing intervals (weekly and biweekly) administered
subcutaneously in patients with rheumatoid arthritis with single DMARD
failure. The doses of 20 and 40 mg adalimumab were selected based on
results of a previous study (DE007). DE011 is a multicenter randomized
placebo-controlled study comparing adalimumab *vs.* placebo with four
periods: 1.) washout period, 2.) placebo-controlled treatment period,
3.) rescue period and 4.) post-study period (Figure 4). After the study
entry screen visit, eligible patients entered a 4-week washout period in
which all disease-modifying anti-rheumatic drugs (DMARDs) were
discontinued. After the washout period, patients were randomized at the
baseline visit to one of five treatment arms.

Patients who experienced an increase in disease activity or had less
than 10% reduction in SJC and TJC compared to baseline, after at least 8
weeks of treatment, had the option to enter the rescue part of the
study. During the rescue part double-blind treatment was stopped, and at
the discretion of the treating physician higher doses of steroids,
non-steroidal anti-inflammatory drugs (NSAIDs), or DMARDs were
prescribed to cover the time until the end of the 26-week
placebo-controlled treatment period.

The main criteria for inclusion are male and female patients ≥18 years
of age with a confirmed diagnosis of RA (as defined by the 1987-revised
ACR criteria), having failed one DMARD treatment, with at least 10
swollen joints (out of 66 assessed) and 12 tender joints (out of 68
assessed), and an erythrocyte sedimentation rate (ESR) ≥ 28 mm/1st
hour or C-reactive protein (CRP) ≥2 mg/dL.

![](media/image6.png){width="5.997916666666667in"
height="3.051388888888889in"}

Figure 4: Design of Study DE011

The main exclusion criteria are evidence of cardiac, pulmonary,
metabolic, renal, hepatic, gastrointestinal conditions, ongoing, recent,
active, or latent infectious diseases, immune deficiency, history of
lymphoma, leukemia or solid malignant tumor, history of tuberculosis or
listeriosis, drug usage, recent joint surgery or injections, or having
previously received any TNF antagonist (e.g., adalimumab, etanercept or
infliximab)

Patients were prohibited from receiving any
anti-rheumatic/anti-inflammatory drugs (i.e. DMARDs), except stable
corticosteroids with a maximum daily dose equivalent to 10 mg of
prednisolone, stable doses of NSAIDs prior to entering the rescue part
of the study, and infrequent use of acetylsalicylic acid in recommended
doses or equivalent treatments for mild pain (e.g., headache) as well as
a regular intake of low-dose acetylsalicylic acid for prophylaxis of
myocardial infarction.

Adalimumab or placebo was administered as a single sc injection (1.6 mL
injectable solution in identical in appearance 2 mL. glass vials) every
week or every other week for up to 26 weeks. Based on the randomization
scheme, patients were to receive 20 or 40 mg of adalimumab per injection
as a total body dose or placebo. Study drug was then injected under the
skin of the abdomen or thigh in accordance with standard medical
practice for sterile sc injection. The final concentrations of
adalimumab were 20 mg/1.6 mL and 40 mg/1.6 mL. Placebo solution was a
buffered vehicle of phosphate, citrate, and mannitol with 0.1% Tween 80.
Each patient received a weekly injection of study drug or placebo to
maintain the blinding.

The primary efficacy assessment was a comparison of the ACR20 response
rates (using CRP as the acute phase reactant) between the individual
adalimumab treatment groups (20, 40, and 80 mg subcutaneous every 2
weeks) and placebo at Week 24. Statistical methodology consists of
Pearson's chi-squared (*χ*^2^) test and analyses of covariance (ANCOVA)
for treatment group differences between adalimumab and placebo during
the placebo-controlled treatment period. Baseline homogeneity of
demographic and baseline characteristics were checked using one-way
analysis of variance (ANOVA), the Kruskal-Wallis test, or a Pearson's
*χ*^2^ test, as appropriate. The primary efficacy analysis was a
comparison of the response rates according to ACR20 in the
intent-to-treat (ITT) population which was the same as the full analysis
set of patients, and patients who did not complete the 26-week
placebo-controlled period were counted as non-responders. Each of the
four adalimumab dosage groups was tested for difference *vs.* placebo
using a two-sided Pearson's *χ*^2^ test. The overall significance level
was α=0.05. Multiplicity of testing (four tests) for the primary
efficacy analysis was taken into account by applying the Bonferroni-Holm
procedure, multiplying by a factor related to the number of comparisons
and the degrees of freedom for the error mean square. Thus requiring a
four-fold lower p-value in order to acquire statistical significance.
All other statistical testing was unadjusted for multiple comparisons.

Analyses of the secondary efficacy endpoints included TJC, SJC,
disability index of the HAQ, ACR50 response, ACR70 response, ACR-N
response, time until ACR20, ACR50, and ACR70 responses, AUC of ACR-N,
ACR20, ACR50, and ACR70 responses, patient and physician global
assessments of disease activity, patient assessment of pain, duration of
morning stiffness, CRP, ESR, SF-36 score, and modified DAS score.
Statistical analyses of secondary efficacy variables (Pearson's *x*^2^
test for ACR50 and ACR70 response, ANCOVA for other secondary efficacy
variables) were exploratory analyses.

B.  **Study Conduct**

A total of 500 patients (100 per arm) were planned for enrollment in
this study conducted at 52 sites in Europe, Australia, and Canada. Eight
hundred twenty-seven (827) patients were screened, 544 patients were
randomized, 481 patients completed the study, and data for 544 patients
were analyzed (a larger number of patients than anticipated). Patients
were randomized in blocks of five patients per block. Patient
disposition is shown in Figure 5 and Table 4.

![](media/image7.png){width="5.364583333333333in"
height="7.020833333333333in"}

> Figure 5 : Patient Disposition in Study DE011

Table 4 : Study DE011 Patient disposition (number \[%\]) by randomized
treatment group (all patients who entered the study)

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<td><h1 id="section-1"></h1>
<h1 id="section-2"></h1></td>
<td colspan="9"><h5 id="adalimumab-2">Adalimumab</h5></td>
<td rowspan="3"><p id="placebo-2" class="heading">Placebo</p></td>
</tr>
<tr class="even">
<td rowspan="3"><h1 id="section-3"></h1>
<h1 id="treatment"> Treatment</h1></td>
<td colspan="4"><strong>20 mg</strong></td>
<td colspan="4"><strong>40 mg</strong></td>
<td rowspan="2"><strong>All</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Q2W</strong></td>
<td colspan="2"><strong>Weekly</strong></td>
<td colspan="2"><strong>Q2W</strong></td>
<td colspan="2"><strong>Weekly</strong></td>
</tr>
<tr class="even">
<td><strong>N=106</strong></td>
<td colspan="2"><strong>N=112</strong></td>
<td colspan="2"><strong>N=113</strong></td>
<td colspan="2"><strong>N=103</strong></td>
<td colspan="2"><strong>N=434</strong></td>
<td><strong>N=110</strong></td>
</tr>
<tr class="odd">
<td><strong>Completed study</strong></td>
<td><strong>95 (90%)</strong></td>
<td colspan="2"><strong>102 (91%)</strong></td>
<td colspan="2"><strong>96 (85%)</strong></td>
<td colspan="2"><strong>95 (92%)</strong></td>
<td colspan="2"><strong>388 (90%)</strong></td>
<td><p><strong>93</strong></p>
<p><strong>(85%)</strong></p></td>
</tr>
<tr class="even">
<td><h1 id="completed-study-on-randomized-therapy">Completed study on
randomized therapy</h1></td>
<td><strong>68 (64)</strong></td>
<td colspan="2"><strong>79 (71)</strong></td>
<td colspan="2"><strong>81 (72)</strong></td>
<td colspan="2"><strong>88 (85)</strong></td>
<td colspan="2"><strong>316 (73)</strong></td>
<td><strong>48(44)</strong></td>
</tr>
<tr class="odd">
<td><h1 id="completed-study-with-rescue-8-weeks">Completed study with
rescue ≥ 8 weeks</h1></td>
<td>27 (26)</td>
<td colspan="2">23 (21)</td>
<td colspan="2">15 (13)</td>
<td colspan="2">7 (7)</td>
<td colspan="2"><strong>72 (17)</strong></td>
<td><strong>45(41)</strong></td>
</tr>
<tr class="even">
<td colspan="11"></td>
</tr>
<tr class="odd">
<td><h1 id="withdrew-early">Withdrew early</h1></td>
<td>11 (10)</td>
<td colspan="2">10 (9)</td>
<td colspan="2">17 (15)</td>
<td colspan="2">8 (8)</td>
<td colspan="2">46 (11)</td>
<td>17(16)</td>
</tr>
<tr class="even">
<td><strong>Withdrawals from study due to :</strong></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td>Adverse event</td>
<td>4 (4)</td>
<td colspan="2">3 (3)</td>
<td colspan="2">6 (5)</td>
<td colspan="2">3 (3)</td>
<td colspan="2">16 (4)</td>
<td>1 (1)</td>
</tr>
<tr class="even">
<td>Lost to follow-up</td>
<td>0 (0)</td>
<td colspan="2">0 (0)</td>
<td colspan="2">1 (1)</td>
<td colspan="2">0 (0)</td>
<td colspan="2">1 (0)</td>
<td>1 (1)</td>
</tr>
<tr class="odd">
<td>Protocol violation</td>
<td>2 (2)</td>
<td colspan="2">2 (2)</td>
<td colspan="2">2 (2)</td>
<td colspan="2">1 (1)</td>
<td colspan="2">7 (2)</td>
<td>1 (1)</td>
</tr>
<tr class="even">
<td>Death</td>
<td>0 (0)</td>
<td colspan="2">0 (0)</td>
<td colspan="2">1 (1)</td>
<td colspan="2">0 (0)</td>
<td colspan="2">1 (0)</td>
<td>1 (1)</td>
</tr>
<tr class="odd">
<td>Withdrawal of consent</td>
<td>1 (1)</td>
<td colspan="2">1 (1)</td>
<td colspan="2">2 (2)</td>
<td colspan="2">1 (1)</td>
<td colspan="2">5 (1)</td>
<td>2 (2)</td>
</tr>
<tr class="even">
<td>Lack of efficacy/progression of disease</td>
<td>4 (4)</td>
<td colspan="2">4 (4)</td>
<td colspan="2">5 (4)</td>
<td colspan="2">3 (3)</td>
<td colspan="2">16 (4)</td>
<td>11(10)</td>
</tr>
<tr class="odd">
<td colspan="11"></td>
</tr>
<tr class="even">
<td>Adverse event (at least possibly drug-related)</td>
<td>3 (3)</td>
<td colspan="2">3 (3)</td>
<td colspan="2">4 (4)</td>
<td colspan="2">2 (2)</td>
<td colspan="2">12 (3)</td>
<td>0</td>
</tr>
</tbody>
</table>

A total of 364 (67%) of 544 randomized patients completed the
placebo-controlled

portion of the adalimumab monotherapy trial. Similar proportions of
subjects completed the study in the drug and placebo arms. However, a
higher percentage of adalimumab-treated patients completed the study
(64 - 85%) on randomized therapy compared to placebo-treated patients
(44%). A total of 120 patients (22%) entered the rescue part during the
placebo-controlled period. However, three of the patients requiring
rescue withdrew prematurely, and 117 patients requiring rescue completed
the study. A higher percentage of placebo-treated patients (41%) than
adalimumab-treated patients (17%) required rescue therapy after the
8^th^ week.

A higher percentage of placebo-treated patients (16%) than
adalimumab-treated patients (11%) withdrew from the study early. This
difference is accounted for by a higher proportion of placebo-treated
patients (10%) than adalimumab-treated patients (4%) withdrawing for
lack of efficacy. Among the 46 adalimumab-treated patients who withdrew
from the study, 16 ( 4% of those randomized) patients withdrew due to
adverse events and 16 ( 4% of those randomized) withdrew due to lack of
efficacy/progression of disease. Among the 17 (16% % of those
randomized) placebo-treated patients who withdrew from the study, 11
(10% of those randomized), the majority, withdrew due to lack of
efficacy/progression of study disease.

Adverse events, at least possibly drug-related, were observed in 3%
(12/434) of adalimumab-treated patients and 0% of placebo-treated
patients. Two deaths occurred in the trial, one among each group, the
adalimumab-treated group and placebo-treated group. Deaths and adverse
events will be reviewed in the Integrated Safety Analysis.

Protocol violations contributing to withdrawals occurred in 2% of
adalimumab-treated patients and 1% of placebo-treated patients.

The demographic characteristics (see Table 5) by randomized treatment
group for all patients who entered the study demonstrated that the
majority were Caucasians and 80% were females with a median age of 54
years, similar to other RA clinical trials. The demographic
characteristics in the various groups were comparable. Participants
manifested long-standing disease (medians 8-10 years) and active
rheumatoid arthritis, as manifested by high mean TJCs (means 34-36) and
SJCs (means all approximately 20) (Table 6 ).

Table 5 : Study DE011 : Demographic characteristics by randomized
treatment group (all patients who entered the study)

![](media/image8.png){width="5.822916666666667in"
height="5.302083333333333in"}

Table 6 : Study DE011 : Duration of RA and ACR components of disease
activity at baseline by randomized treatment group (full-analysis set)

![](media/image9.png){width="5.802083333333333in"
height="5.291666666666667in"}

> **C. Efficacy Analysis**

1.  **Efficacy Endpoints**

The primary efficacy endpoint was the ACR20 response at Week 26.
Patients were classified as "**responders**" if all of the following
criteria were met:

-   A []{.underline}20% improvement in tender joint count.

-   A []{.underline}20% improvement in swollen joint count.

-   A []{.underline}20% improvement in at least three of the five
    remaining ACR core set measures:

> 1\. Patient assessment of pain.
>
> 2\. Patient global assessment of disease activity.
>
> 3\. Physician global assessment of disease activity.
>
> 4\. Patient self-assessed disability (disability index of the Health
>
> Assessment Questionnaire \[HAQ\]).
>
> 5\. Acute phase reactant: ESR or C-Reactive Protein.

Patients were considered to be **non-responders** (efficacy failures) if
they:

-   failed to meet or improve beyond the American College of
    Rheumatology 20% (ACR20) improvement criteria at Week 26

-   withdrew from the study prior to Weeks 26 (including ACR20
    responders),

-   switched to rescue medication

Rescue medication was permitted after 8 weeks if patients experienced an
increase in disease activity or had less than 10% reduction in SJC and
TJC compared to baseline. Leflunomide was the preferred rescue treatment
if available in the site's given country. Additional rescue medications
permitted through the remainder of the 26-week placebo controlled
treatment period included: higher doses of NSAIDs, corticosteroids, or
DMARDs.

Secondary efficacy endpoints included changes in SJC, TJC, and
disability index of the HAQ from baseline to Week 26; ACR50, ACR70,
numeric ACR (ACR-N), disease activity score (DAS), patient and physician
global assessments of disease activity, patient assessment of pain,
morning stiffness, short form health survey (SF-36), erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor
(RF), and parameters derived from the variables mentioned above.

Serum adalimumab and human anti-human antibodies (HAHAs) concentrations
were measured.

**2. Efficacy Analysis**

The full analysis set comprised all randomized patients who received at
least one injection of study drug and for whom any assessment of
efficacy under double-blind treatment was available. This was the case
for a total of 544 patients enrolled in this study: 434 patients were
administered adalimumab and 110 patients were administered placebo.

A dose response for ACR20 response rates was observed across the
adalimumab treatment groups at Week 26, with the lowest response rate in
the 20 mg q2w group (33%) and the highest observed in the 40 mg weekly
group (54%). A summary of the efficacy parameters measured during the
study period is included in Table 7. The ACR20 response at the dosage
requested for adalimumab approval, 40 mg q2w, demonstrated statistically
significant superiority over placebo, 43% for adalimumab compared to 20%
for placebo (p ≤ 0.001). The 40 mg weekly treatment group showed a
higher ACR20 response at Week 26 than the 20 mg q2w treatment group
(nominal p=0.011) and the 20 mg weekly group (nominal p=0.038). All
other between-group adalimumab comparisons were not statistically
significantly different. It should be noted that these analyses, and all
future presentations of between adalimumab group differences, are
exploratory since the study was not designed to detect significant
differences between adalimumab treatment groups.

The primary efficacy assessment for this study was a comparison of the
ACR20 response rates (using CRP as the acute phase reactant) between
each of the adalimumab treatment groups and placebo at Week 26. After 26
weeks of treatment, every adalimumab treatment group (weekly and q2week
treatment with 20 or 40 mg) was statistically significantly superior
(p[]{.underline}0.05) to placebo for the ACR20 response (20 mg q2w:
p=0.006; 20 mg weekly: p []{.underline}0.001; 40 mg q2w:
p[]{.underline}0.001; 40 mg weekly: p[]{.underline}0.001). These
p-values are significant even when judged against the Bonferroni-Holm
procedure.

Analyses of the secondary efficacy endpoints included TJC, SJC,
disability index of the HAQ, ACR50 response, ACR70 response, ACR-N
response, time until ACR20, ACR50, and ACR70 responses, AUC of ACR-N,
ACR20, ACR50, and ACR70 responses, patient and physician global
assessments of disease activity, patient assessment of pain, duration of
morning stiffness, CRP, ESR, SF-36 score, and modified DAS score.
Statistical analyses of secondary efficacy variables (Pearson's *x*^2^
test for ACR50 and ACR70 response, ANCOVA for other secondary efficacy
variables) were exploratory analyses.

Table 7 : Study DE011 : Components of ACR 20 Response Index

(Median Percentage Improvement at Week 26 Compared to Baseline ^a^)

+----------------------+--------+--------+---+--------+--------+---+--------+
|                      | **     |        |   |        |        | * |        |
|                      | Adalim |        |   |        |        | * |        |
|                      | umab** |        |   |        |        | P |        |
|                      |        |        |   |        |        | l |        |
|                      |        |        |   |        |        | a |        |
|                      |        |        |   |        |        | c |        |
|                      |        |        |   |        |        | e |        |
|                      |        |        |   |        |        | b |        |
|                      |        |        |   |        |        | o |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| #   {#section-4}     | **20   |        |   | **40   |        |   |        |
|                      | mg**   |        |   | mg**   |        |   |        |
| # Efficacy Parameter |        |        |   |        |        |   |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
|                      | *      | **we   |   | *      | **we   |   |        |
|                      | *eow** | ekly** |   | *Q2w** | ekly** |   |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| #  N =               | *      | *      |   | *      | *      | * |        |
|                      | *106** | *112** |   | *113** | *103** | * |        |
| #                    |        |        |   |        |        | 1 |        |
|  ACR 20 response ^o^ |        |        |   |        |        | 1 |        |
|                      |        |        |   |        |        | 0 |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
|                      | *      | **(    |   | **(43  | **(54  | * |        |
|                      | *(33%) | 38%)^\ |   | %)^\*\ | %)^\*\ | * |        |
|                      | ^\*^** | *\*^** |   | *\*^** | *\*^** | ( |        |
|                      |        |        |   |        |        | 2 |        |
|                      |        |        |   |        |        | 0 |        |
|                      |        |        |   |        |        | % |        |
|                      |        |        |   |        |        | ) |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| ## TJC mea           | **42%  | **4    |   | *      | **5    | * |        |
| n percent change ^c^ | ^\*^** | 7%^\*\ |   | *50%^\ | 7%^\*\ | * |        |
|                      |        | *\*^** |   | *\*^** | *\*^** | 1 |        |
|                      |        |        |   |        |        | 3 |        |
|                      |        |        |   |        |        | % |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| ## SJC mea           | **33%  | **44%  |   | **43%  | **5    | * |        |
| n percent change ^c^ | ^\*^** | ^\*\   |   | ^\*\   | 3%^\*\ | * |        |
|                      |        | *\*^** |   | *\*^** | *\*^** | 1 |        |
|                      |        |        |   |        |        | 4 |        |
|                      |        |        |   |        |        | % |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| 1.Pain VAS ^c^       | **22   | **34   |   | **44   | **57   | * |        |
|                      | ^ns^** | ^\*\   |   | ^\*\   | ^\*\   | * |        |
|                      |        | *\*^** |   | *\*^** | *\*^** | 8 |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| 2\. Patient global   | **21   | **36   |   | **40   | **57   | * |        |
| assessment ^c^       | ^ns^** | ^\*\   |   | ^\*\   | ^\*\   | * |        |
|                      |        | *\*^** |   | *\*^** | *\*^** | 9 |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| 3\. Physician global | **25   | **44   |   | **52   | **62   | * |        |
| assessment ^c^       | ^\     | ^\*\   |   | ^\*\   | ^\*\   | * |        |
|                      | *\*^** | *\*^** |   | *\*^** | *\*^** | 1 |        |
|                      |        |        |   |        |        | 2 |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| 4\. HAQ ^c^          | **10   | **15   |   | **13   | **27   | * |        |
|                      | ^\     | ^\*\   |   | ^\*\   | ^\*\   | * |        |
|                      | *\*^** | *\*^** |   | *\*^** | *\*^** | 0 |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| 5\. Acute phase      | **20   | **47   |   | **49   | **55   | * |        |
| reactant ^c^         | ^ns^** | ^\*^** |   | ^\*\   | ^\*\   | * |        |
|                      |        |        |   | *\*^** | *\*^** | - |        |
| CRP                  |        |        |   |        |        | 2 |        |
|                      |        |        |   |        |        | * |        |
|                      |        |        |   |        |        | * |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| Duration of morning  | **50   | **67   | * |        | **88   |   | **33** |
| stiffness            | ^ns^** | ^\     | * |        | ^\*\   |   |        |
|                      |        | *\*^** | 7 |        | *\*^** |   |        |
|                      |        |        | 5 |        |        |   |        |
|                      |        |        | ^ |        |        |   |        |
|                      |        |        | \ |        |        |   |        |
|                      |        |        | * |        |        |   |        |
|                      |        |        | \ |        |        |   |        |
|                      |        |        | * |        |        |   |        |
|                      |        |        | \ |        |        |   |        |
|                      |        |        | * |        |        |   |        |
|                      |        |        | ^ |        |        |   |        |
|                      |        |        | * |        |        |   |        |
|                      |        |        | * |        |        |   |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| Due to the multiple  |        |        |   |        |        |   |        |
| testing (four        |        |        |   |        |        |   |        |
| tests), the          |        |        |   |        |        |   |        |
| Bonferroni-Holm      |        |        |   |        |        |   |        |
| procedure was        |        |        |   |        |        |   |        |
| applied to keep the  |        |        |   |        |        |   |        |
| overall level of     |        |        |   |        |        |   |        |
| significance         |        |        |   |        |        |   |        |
| =0.05 for the     |        |        |   |        |        |   |        |
| primary efficacy     |        |        |   |        |        |   |        |
| parameter..          |        |        |   |        |        |   |        |
+----------------------+--------+--------+---+--------+--------+---+--------+
| **^\*^ Comparison    |        |        |   |        |        |   |        |
| versus placebo       |        |        |   |        |        |   |        |
| (2-sided) p ≤        |        |        |   |        |        |   |        |
| 0.05.**              |        |        |   |        |        |   |        |
|                      |        |        |   |        |        |   |        |
| **^\*\*^ Comparison  |        |        |   |        |        |   |        |
| versus placebo       |        |        |   |        |        |   |        |
| (2-sided) p ≤        |        |        |   |        |        |   |        |
| 0.01.**              |        |        |   |        |        |   |        |
|                      |        |        |   |        |        |   |        |
| **^\*\*\*^           |        |        |   |        |        |   |        |
| Comparison versus    |        |        |   |        |        |   |        |
| placebo (2-sided) p  |        |        |   |        |        |   |        |
| ≤ 0.001.**           |        |        |   |        |        |   |        |
|                      |        |        |   |        |        |   |        |
| **^ns^ not           |        |        |   |        |        |   |        |
| significant**        |        |        |   |        |        |   |        |
|                      |        |        |   |        |        |   |        |
| **^a^ Negative       |        |        |   |        |        |   |        |
| values indicate      |        |        |   |        |        |   |        |
| worsening**          |        |        |   |        |        |   |        |
|                      |        |        |   |        |        |   |        |
| **^o^ Observed       |        |        |   |        |        |   |        |
| values;              |        |        |   |        |        |   |        |
| non-responders       |        |        |   |        |        |   |        |
| imputation;          |        |        |   |        |        |   |        |
| comparisons vs       |        |        |   |        |        |   |        |
| placebo by Pearson's |        |        |   |        |        |   |        |
| chi-square test**    |        |        |   |        |        |   |        |
|                      |        |        |   |        |        |   |        |
| **^c^ LOCF; Median   |        |        |   |        |        |   |        |
| percentage           |        |        |   |        |        |   |        |
| improvement          |        |        |   |        |        |   |        |
| -comparisons vs      |        |        |   |        |        |   |        |
| placebo by ANCOVA    |        |        |   |        |        |   |        |
| with factor          |        |        |   |        |        |   |        |
| treatment group and  |        |        |   |        |        |   |        |
| baseline value as    |        |        |   |        |        |   |        |
| covariate            |        |        |   |        |        |   |        |
| Comparisons versus   |        |        |   |        |        |   |        |
| placebo (2-sided)**  |        |        |   |        |        |   |        |
+----------------------+--------+--------+---+--------+--------+---+--------+

After 26 weeks of treatment, each adalimumab dose was associated with a
greater median percentage improvement (negative change from baseline) in
TJC, SJC, and the disability index (HAQ) than placebo. The TJC, SJC,
pain (VAS), patient global assessment, physician global assessment,
acute phase reactant, duration of morning stiffness, and the disability
index of the HAQ responses at the dosage requested for adalimumab
approval, 40 mg q2w, demonstrated statistically significant superiority
for adalimumab compared to placebo (p ≤ 0.01).

Since rescue was allowed after Week 8 for patients experiencing lack of
efficacy, it is informative to examine response rates at Week 8, when
all subjects were still receiving assigned study drug. Table 8 compares
the ACR20 response at Week 8 (the time period at which rescue medication
was initially permitted) and Week 26 (the time period for appraisal of
the primary efficacy endpoint). At Week 8, before rescue medication was
allowed, the majority of the ACR20 responses to adalimumab at the
proposed dosage of 40 mg biweekly had already been demonstrated, and
only a few additional responses occur over the next 18 weeks.

Table 8 : Study DE011 : Comparison of ACR20 Response At Week 8 and Week
26

<table style="width:100%;">
<colgroup>
<col style="width: 30%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="8"><strong>Adalimumab</strong></td>
<td rowspan="2"><strong>Placebo</strong></td>
</tr>
<tr class="even">
<td><h1 id="section-5"></h1>
<h1 id="acr-20-responders-at">ACR 20 Responders at</h1></td>
<td><p><strong>20 mg</strong></p>
<p><strong>q2w</strong></p></td>
<td colspan="2"><p><strong>20 mg</strong></p>
<p><strong>weekly</strong></p></td>
<td colspan="2"><p><strong>40 mg</strong></p>
<p><strong>q2w</strong></p></td>
<td colspan="3"><p><strong>40 mg</strong></p>
<p><strong>weekly</strong></p></td>
</tr>
<tr class="odd">
<td><h1 id="week-8">Week 8</h1></td>
<td colspan="2"><p>43</p>
<p>(41%)</p></td>
<td colspan="2"><p>46</p>
<p>(41%)</p></td>
<td colspan="2"><p>46</p>
<p>(41%)</p></td>
<td><p>45</p>
<p>(44%)</p></td>
<td colspan="2"><p>16</p>
<p>(15%)</p></td>
</tr>
<tr class="even">
<td><h1 id="week-26">Week 26</h1></td>
<td colspan="2"><p>38/106</p>
<p>(36%)</p></td>
<td colspan="2"><p>44/112</p>
<p>(39%)</p></td>
<td colspan="2"><p>52/113</p>
<p>(<strong>46%)</strong></p></td>
<td><p>55/103</p>
<p>(<strong>53%)</strong></p></td>
<td colspan="2"><p>21/110</p>
<p><strong>(19%)</strong></p></td>
</tr>
</tbody>
</table>

Figure 6 displays graphically the observed ACR20 responses over time for
the full analysis set of patients. This figure demonstrates that the
majority of responders had achieved an ACR20 response by the Week 2
study visit. In addition, the separation between adalimumab-treated
patients and placebo-treated patients continues through Week 26.

![](media/image10.png){width="5.916666666666667in"
height="4.322916666666667in"}

Figure 6 : Study DE011 : Responder rates according to ACR20 (observed
values; full analysis set)

After 26 weeks of treatment, each of the four adalimumab treatment
groups had higher ACR50, ACR70, and ACR-N responses than the placebo
group. Statistically significant differences (p ≤ 0.05) were observed
for the recommended dose of adalimumab, 40 mg q2w, compared to placebo
for the ACR20, ACR50 ACR70, and ACR-N responses (Table 9).

Table 9 : Study DE011 : Summary of Major Efficacy Results at Week 26 --
Number and Percentage of Patients Responding By Randomized Treatment
Group (full analysis set)

+----------------+---------+---------+---------+---------+-----------+
|                | **Adali |         |         |         | **        |
|                | mumab** |         |         |         | Placebo** |
+----------------+---------+---------+---------+---------+-----------+
| #              | N=106   | N=112   | N=113   | N=103   | N=110     |
|   {#section-6} |         |         |         |         |           |
+----------------+---------+---------+---------+---------+-----------+
| # Effi         | **20    | **20    | **40    | **40    |           |
| cacy Parameter | mg**    | mg**    | mg**    | mg**    |           |
|                |         |         |         |         |           |
|                | **eow** | **w     | **eow** | **w     |           |
|                |         | eekly** |         | eekly** |           |
+----------------+---------+---------+---------+---------+-----------+
| **ACR 20       | 38/106  | 44/112  | 52/113  | 55/103  | 21/110    |
| response** ^o^ |         |         |         |         |           |
|                | (       | (       | (**43   | (**54%) | (20%)     |
|                | 33%)^a^ | 38%)^a^ | %)**^a^ | **^abc^ |           |
+----------------+---------+---------+---------+---------+-----------+
|                |         |         |         |         |           |
+----------------+---------+---------+---------+---------+-----------+
| # ACR 5        | 20/106  | 23/112  | 25/113  | 36/103  | 9/110     |
| 0 response ^o^ |         |         |         |         |           |
|                | (       | (       | (       | (       | (8%)      |
|                | 19%)^a^ | 21%)^a^ | 22%)^a^ | **35%)* |           |
|                |         |         |         | *^abcd^ |           |
+----------------+---------+---------+---------+---------+-----------+
| # ACR 7        | 9/106   | 11/112  | 14/113  | 19/103  | 2/110     |
| 0 response ^o^ |         |         |         |         |           |
|                | (9%)^a^ | (       | (       | (**18*  | (2%)      |
|                |         | 10%)^a^ | 12%)^a^ | *%)^ab^ |           |
+----------------+---------+---------+---------+---------+-----------+
| #              | N       | N       | N       | N       | N         |
|   {#section-7} |         |         |         |         |           |
|                | Mean ±  | Mean ±  | Mean ±  | Mean ±  | Mean ± SD |
|                | SD      | SD      | SD      | SD      |           |
+----------------+---------+---------+---------+---------+-----------+
| **ACR-N        | N=68    | N=78    | N=82    | N=88    | N=48      |
| response** ^o^ | 25.6±37 |         | 26.7±44 |         |           |
|                | .5^a,f^ | 24.0±   | .4^a,f^ | 29.0±46 | 8.3±52.6  |
|                |         | 43.1^f^ |         | .1^a,f^ |           |
+----------------+---------+---------+---------+---------+-----------+
| ^a^            |         |         |         |         |           |
| Statistically  |         |         |         |         |           |
| significant    |         |         |         |         |           |
| difference     |         |         |         |         |           |
| from placebo   |         |         |         |         |           |
| based on       |         |         |         |         |           |
| Pearson's      |         |         |         |         |           |
| *x*^2^ test    |         |         |         |         |           |
| (p\<0.05)      |         |         |         |         |           |
|                |         |         |         |         |           |
| ^b^            |         |         |         |         |           |
| Statistically  |         |         |         |         |           |
| significant    |         |         |         |         |           |
| difference     |         |         |         |         |           |
| from 20 mg q2w |         |         |         |         |           |
| based on       |         |         |         |         |           |
| Pearson's      |         |         |         |         |           |
| *x*^2^ test    |         |         |         |         |           |
| (p\<0.05)      |         |         |         |         |           |
|                |         |         |         |         |           |
| ^c^            |         |         |         |         |           |
| Statistically  |         |         |         |         |           |
| significant    |         |         |         |         |           |
| difference     |         |         |         |         |           |
| from 20 mg     |         |         |         |         |           |
| weekly based   |         |         |         |         |           |
| on Pearson's   |         |         |         |         |           |
| *x*^2^ test    |         |         |         |         |           |
| (p\<0.05)      |         |         |         |         |           |
|                |         |         |         |         |           |
| ^d^            |         |         |         |         |           |
| Statistically  |         |         |         |         |           |
| significant    |         |         |         |         |           |
| difference     |         |         |         |         |           |
| from 40 mg q2w |         |         |         |         |           |
| based on       |         |         |         |         |           |
| Pearson's      |         |         |         |         |           |
| *x*^2^ test    |         |         |         |         |           |
| (p\<0.05)      |         |         |         |         |           |
|                |         |         |         |         |           |
| ^f^            |         |         |         |         |           |
| Statistically  |         |         |         |         |           |
| significantly  |         |         |         |         |           |
| different from |         |         |         |         |           |
| baseline based |         |         |         |         |           |
| on 95%         |         |         |         |         |           |
| confidence     |         |         |         |         |           |
| intervals (p ≤ |         |         |         |         |           |
| 0.05).         |         |         |         |         |           |
+----------------+---------+---------+---------+---------+-----------+

^o^ Observed values, means

Study DE011 provides baseline and LOCF Week 26 HAHA (human anti-human
antibody, i.e., anti-adalimumab antibody levels) data for 432
monotherapy adalimumab-treated patients (no concomitant MTX), the
largest number of single study patients evaluated for HAHAs. Twelve
percent of patients in this study developed HAHAs. Among the
adalimumab-treated patients, the ACR20 response is lower (nominal p=
0.0048) among the HAHA positive adalimumab-treated patients (26%) than
among all the HAHA negative adalimumab-treated patients (46%). The ACR20
response is also lower (nominal p=0.104) at the proposed dosage of 40 mg
biweekly among the HAHA positive adalimumab-treated patients (30%) than
among the HAHA negative adalimumab-treated patients (50%) (Table 10).

Table 10 : Study DE011: Relationship between HAHA and ACR20 Response at
Week 26

+-------------------+-------------------+------------------+-----------+
|                   | [HAHA             | [HAHA            | P-value   |
|                   | Posi              | Negat            |           |
|                   | tive]{.underline} | ive]{.underline} |           |
|                   |                   |                  |           |
|                   | N ACR20 (%)       | N ACR20 (%)      |           |
+-------------------+-------------------+------------------+-----------+
| All Patients      | 54. 14 (26%)      | 488. 196 (40%)   | 0\. 0416  |
|                   |                   |                  |           |
| Adalimumab        | > 54 14 (26%)     | > 378 175 (46%)  | 0.0048    |
| patients          |                   |                  |           |
|                   | 19. 7 (37%)       | 87. 31 (35%)     | 0.921     |
| 20 mg biweekly    |                   |                  |           |
|                   | > 11 1 (9%)       | ```{=html}       | 0.048     |
| 20 mg weekly      | >                 | <!-- -->         |           |
|                   | > 20 6 (30%)      | ```              | 0.104     |
| 40 mg biweekly    | >                 | 101. 43 (43%)    |           |
|                   | > 4 0 (0%)        |                  | 0.042     |
| 40 mg weekly      | >                 | > 92 46 (50%)    |           |
|                   | > 0 0 (0%)        | >                | \-\-\--   |
| Placebo           |                   | > 98 55 (56%)    |           |
|                   |                   | >                |           |
|                   |                   | > 110 21 (19%)   |           |
+-------------------+-------------------+------------------+-----------+

Comparison of the dosing interval of adalimumab administration reveals a
higher incidence of the development of HAHAs (nominal p = 0.0006)
associated with biweekly administration (18%) compared to weekly
administration (7%). To control for differences in overall dose,
patients who received equal doses of adalimumab over a 2-week interval
were compared, i.e. a weekly (20 mg qw) or a biweekly (40 mg q2w)
injection. HAHAs were more common among the patients receiving the
biweekly dosage(18%) than those receiving the weekly dosage (10%)
(nominal p= 0.0816) (Table 11).

Table 11 : Study DE011 : Relationship of Dose and Dosing Interval of
Adalimumab Administration and HAHA Development

+-----------------------------+---------------------------+------------+
|                             | N HAHA + (%)              | P-value    |
+-----------------------------+---------------------------+------------+
| All patients                | > 214 15 (7%)             | 0.0006     |
|                             | >                         |            |
| Weekly                      | > 218 39 (18%)            | 0.0816     |
|                             | >                         |            |
| Biweekly                    | > 112 11 (10%)            |            |
|                             | >                         |            |
| Subgroup                    | > 112 20 (18%)            |            |
|                             |                           |            |
| 20 mg weekly                |                           |            |
|                             |                           |            |
| 40 mg biweekly              |                           |            |
+-----------------------------+---------------------------+------------+

3.  **Summary of Efficacy Data**

In this trial, the ACR20 response at Week 26, the primary efficacy
parameter, was shown to be statistically superior to placebo for all
four adalimumab treatment groups. A dose-response relationship was
observed for ACR20 response rates across the adalimumab treatment groups
at Week 26, with the lowest response rate for the 20 mg q2w group (33%),
and the highest response rate for the 40 mg weekly group (54%). The
ACR20 response rate at Week 26 for the adalimumab 40 mg q2w treatment
group (43%), the proposed approval dosage, was statistically superior to
the placebo-treated group (20%). The majority of responders had achieved
an ACR20 response by the Week 2 study visit, and separation between
adalimumab-treated patients and placebo-treated patients continued
through Week 26.

Among adalimumab-treated patients, biweekly administration of adalimumab
resulted in a higher incidence of HAHA-positivity than weekly
administration, and HAHA-positivity was associated with a reduced
frequency of ACR20 responses.

IV\. Study DE019 -- Adalimumab Plus Background Stable Dose Methotrexate
Trial

A. Clinical Trial Design

Study DE019 is a multicenter double-blind, randomized,
placebo-controlled 52 week phase III trial of adalimumab add-on therapy
to background methotrexate (MTX) conducted to investigate the efficacy,
safety, immunogenicity, and effect on immune response of subcutaneous
(sc) injections of adalimumab (20 mg weekly or 40 mg biweekly \[q2w\])
compared to placebo weekly in patients with active RA treated
concomitantly with MTX. A secondary objective was to investigate the
retardation of disease progression at 52 weeks as detected by x-ray. The
trial is composed of three parts: 1) a washout period and 2) a 52-week
double-blind placebo-controlled period conducted at 89 sites in the
United States and Canada (Figure 7), and 3) a 52-week open-label period.
Patients without an ACR20 response by Week 16 could receive rescue
medication if requested by the patient and permitted by the
investigator-physician. After completing the 52-week placebo-controlled
treatment period, patients could enter a 52-week open-label period with
every other week 40 mg adalimumab treatment. Results from the
double-blind placebo-controlled period of this study (1-year) are
presented in this report. The doses of 20 mg weekly and 40 mg eow were
determined from the 12-week double-blinded period results of Study
DE007.

![](media/image11.png){width="6.0in" height="2.573611111111111in"}

**MTX R ACR**

**Stable Dose Rescue 20**

**permitted**

Figure 7 : Study DE019: Study Design of the 52-Week Placebo-Controlled
Study

The planned sample size was 600 randomized patients with RA (as defined
by the 1987 ACR criteria) who had been treated concomitantly with MTX
for a minimum of 3 months, prior to study entry. Patients were screened
for study eligibility based on the inclusion/exclusion criteria. At the
baseline visit patients were randomized to one of three equal groups of
200 patients to receive one of three study treatments consisting of
either adalimumab or placebo via subcutaneous injection for up to 52
weeks:

> 1\. Weekly 20 mg adalimumab
>
> 2\. Biweekly 40 mg adalimumab and on alternate weeks placebo
>
> 3\. Weekly placebo.

Adalimumab or placebo was self-administered (or given by a qualified
person) as a single sc injection (1.6 mL injectable solution in
identical in appearance 2 mL. glass vials) every week or every other
week for up to 52 weeks. The concentrations of adalimumab solution were
20 mg/1.6 mL and 40 mg/1.6 mL. Placebo solution was a buffered vehicle
with Tween 80. Patients returned for periodic examinations at Weeks 2,
4, 8, 12, 16, 20, 24, 32, 40, 48, and 52.

Eligibility consisted of RA patients with these inclusion criteria:

-   Age 18 years and older, and for women of child-bearing potential
    demonstration of a negative pregnancy test (serum). .

```{=html}
<!-- -->
```
-   Met the ACR criteria for diagnosis of active RA and had at both the
    screening and baseline visits []{.underline}6 swollen joints,
    []{.underline}9 tender joints, and a C-reactive protein (CRP)
    []{.underline}1 mg/dL, despite a minimum of 3 months of treatment
    with MTX.

-   Taking a stable dose of MTX (oral, intramuscular, or sc) for at
    least 4 weeks prior to the screening visit with insufficient
    efficacy.

```{=html}
<!-- -->
```
-   Not taking DMARDs other than MTX (required a washout period during
    which all previous DMARDs \[except MTX\] were discontinued)

-   Rheumatoid factor (RF) positivity or at least one joint erosion on
    x-ray. *\[Based on changes made in Amendment B, patients were
    eligible if they had both RF positivity and a CRP* []{.underline}*1
    mg/dL, or at least one joint erosion on x-ray.\]*

-   Patients receiving stable daily glucocorticoids equivalent to
    []{.underline}10 mg of prednisone

> The dose of MTX was to remain constant during the 52-week double-blind
> period unless toxicity occurred.

The main exclusion criteria are evidence of cardiac, pulmonary,
metabolic, renal, hepatic, gastrointestinal conditions, inflammatory
joint or bowel disease, ongoing, recent, active, or latent infectious
diseases, immune deficiency, history of lymphoma, leukemia or solid
malignant tumor, history of tuberculosis or listeriosis, drug usage,
alcohol abuse, recent joint surgery or injections, recent treatment with
an investigational drug, laboratory values suggestive of possible MTX
toxicity, having previously received any anti-TNF antagonist, pregnancy
or breast-feeding.

At baseline and at every subsequent examination during the 52-week
double-blind placebo-controlled period, joint assessments (tender and
swollen joint counts) were performed by a blinded assessor, who was
independent of the treating physician.

Study DE019 has three Primary Efficacy Endpoints:

> 1\. Comparison of ACR20 response rates at week 24

2\. Inhibition of radiographic progression at week 52

3.  Disability index of HAQ at week 52

**1) ACR20 response rates at Week 24** was the highest hierarchical
primary efficacy outcome and was tested at the = 0.05 level of
significance, Comparisons of responder rates were performed using
Pearson's *x*^2^ test per proposed analysis plan.

Observed data refers to patients with data available at the time point
of analysis. Missing information for that time point, regardless of the
reason, was not counted.

Observed data for ACR20 refers to patients with data available at the
time point of analysis, but subjects were assessed as non- responder
who:

-   did not meet all of the ACR criteria on two consecutive visits at or
    after Week 12

-   took additional DMARDs or increased MTX dose at or after the Week 16
    assessments

-   withdrew from the study prior to the measured time point (including
    ACR responders).

Comparisons were performed in sequence, using the closure principle to
adjust for multiple comparisons*. \[the first comparison was between
ACR20 responder rates for*

*all adalimumab-treated patients and placebo-treated patients, with
subsequent comparisons between specific dose groups and placebo.\]*

**2) Modified total Sharp x-ray score changes at Week 52** was the
second hierarchical primary efficacy outcome. Radiographs of the
hands/wrists and feet of each patient were obtained at screening and at
Weeks 24, 52, and last visit for those who terminated early. The change
in modified total Sharp x-ray score at Week 52 compared to baseline was
designated as a primary endpoint. Digitized images of each radiograph
were scored by two physicians (Dr. John Sharp and Dr. Carl Winalski).
The assessors were blinded to study treatment and the chronological
order of the images. Missing values were imputed using linear
extrapolation from baseline and the last during-study evaluation. A
secondary analysis was performed following the LOCF approach to impute
missing values. The difference among all treatment groups was to be
assessed using analysis of covariance (ANCOVA) with the baseline value
as the covariate.

The protocol specified that a Shapiro-Wilk test would be performed on
the data to assess normality. If the results of the Shapiro-Wilk test
indicated a non-normal distribution with a p value of ≤ 0.05, the data
were to be assessed using an analysis of ranks.

**3) Disability index of the HAQ change at Week 52**, the third primary
efficacy endpoint was to be performed if the modified total Sharp x-ray
score was significant at Week 52 (p ≤ 0.05). The difference among all
treatment groups was to be assessed using ANCOVA with the baseline value
as the covariate. If this was significant (p ≤0.05), pairwise
comparisons between each active treatment group and placebo were to be
evaluated using the same method.

Secondary efficacy variables consisted of classifying patients according
to their level of improvement in disability index of the HAQ scores.
Categories included an improvement of 0.22 (the minimally clinically
significant change as defined by Goldsmith et al 1993) and 0.50
(considered a major improvement). This analysis utilizes LOCF approach
for missing data.

Every effort was made to follow these patients and obtain x-rays even if
they withdrew from the study.

**B. Study Conduct**

A total of 619 patients (approximately 200 per arm) were randomized and
enrolled in the

double-blinded, placebo-controlled period of this study at 89 sites in
the United States and Canada in equal proportions in the three study
arms (Figure 8). Approximately three-quarters of the patients completed
the 52 week study, with a somewhat higher proportion completing in the
adalimumab groups (78%) than in the placebo group (70%). A higher
percentage of placebo-treated patients (30%) than adalimumab-treated
patients (22%) withdrew early from the 52 week study. A higher
proportion of patients discontinued treatment due to adverse events
among adalimumab-treated patients (10%) than among placebo-treated
patients (7%) (Table 12).

.

> ![](media/image12.png){width="4.883333333333334in"
> height="7.145833333333333in"}
>
> Figure 8 : Study DE019 : Patient Disposition

Table 12 : Study DE019 :Patient Disposition and Efficacy Assessment of
Primary Endpoints At 24 and 52 Weeks

+-------------------------+----+-----+----------+----------+---+----------+
| **Planned enrollment N  |    | *   |          |          |   |          |
| = 600**                 |    | *Pa |          |          |   |          |
|                         |    | tie |          |          |   |          |
|                         |    | nts |          |          |   |          |
|                         |    | Sc  |          |          |   |          |
|                         |    | ree |          |          |   |          |
|                         |    | ned |          |          |   |          |
|                         |    | N = |          |          |   |          |
|                         |    | 79  |          |          |   |          |
|                         |    | 5** |          |          |   |          |
+-------------------------+----+-----+----------+----------+---+----------+
| **Enrolled &            | *  |     |          |          |   |          |
| randomized**            | *N |     |          |          |   |          |
|                         | =  |     |          |          |   |          |
|                         | 6  |     |          |          |   |          |
|                         | 19 |     |          |          |   |          |
|                         | ** |     |          |          |   |          |
+-------------------------+----+-----+----------+----------+---+----------+
| # Com                   | *  |     |          |          |   |          |
| pleted study (52 weeks) | *N |     |          |          |   |          |
|                         | =  |     |          |          |   |          |
|                         | 4  |     |          |          |   |          |
|                         | 67 |     |          |          |   |          |
|                         | ** |     |          |          |   |          |
+-------------------------+----+-----+----------+----------+---+----------+
| # Withdrew ea           | *  |     |          |          |   |          |
| rly {#withdrew-early-1} | *N |     |          |          |   |          |
|                         | =  |     |          |          |   |          |
|                         | 1  |     |          |          |   |          |
|                         | 52 |     |          |          |   |          |
|                         | ** |     |          |          |   |          |
+-------------------------+----+-----+----------+----------+---+----------+
| #  T                    | ** |     |          |          |   |          |
| reatment {#treatment-1} | Ad |     |          |          |   |          |
|                         | al |     |          |          |   |          |
|                         | im |     |          |          |   |          |
|                         | um |     |          |          |   |          |
|                         | ab |     |          |          |   |          |
|                         | ** |     |          |          |   |          |
+-------------------------+----+-----+----------+----------+---+----------+
|                         | ** |     | **40     | **All**  | * |          |
|                         | 20 |     | mg**     |          | * |          |
|                         | mg |     |          | ###      | P |          |
|                         | ** |     | **Q2W**  | ##### Ad | l |          |
|                         |    |     |          | alimumab | a |          |
|                         | ** |     | *        |  {#adali | c |          |
|                         | We |     | *N=207** | mumab-3} | e |          |
|                         | ek |     |          |          | b |          |
|                         | ly |     |          | *        | o |          |
|                         | ** |     |          | *N=419** | * |          |
|                         |    |     |          |          | * |          |
|                         | *  |     |          |          |   |          |
|                         | *N |     |          |          | * |          |
|                         | =2 |     |          |          | * |          |
|                         | 12 |     |          |          | N |          |
|                         | ** |     |          |          | = |          |
|                         |    |     |          |          | 2 |          |
|                         |    |     |          |          | 0 |          |
|                         |    |     |          |          | 0 |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| # Comp                  | *  |     | **173    | **354    | * |          |
| leted study (24 weeks)  | *1 |     | (85%)**  | (86%)**  | * |          |
|                         | 81 |     |          |          | 1 |          |
|                         | (  |     |          |          | 5 |          |
|                         | 87 |     |          |          | 5 |          |
|                         | %) |     |          |          | ( |          |
|                         | ** |     |          |          | 7 |          |
|                         |    |     |          |          | 8 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| **Withdrew early**      | ** |     | **32     | **60     | * |          |
|                         | 28 |     | (15%)**  | (14%)**  | * |          |
|                         | (  |     |          |          | 4 |          |
|                         | 13 |     |          |          | 5 |          |
|                         | %) |     |          |          | ( |          |
|                         | ** |     |          |          | 2 |          |
|                         |    |     |          |          | 3 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| **Withdrawals from      |    |     |          |          |   |          |
| study:**                |    |     |          |          |   |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Adverse event           | 9  |     | 17 (8%)  | **26     | * |          |
|                         | (4 |     |          | (6%)**   | * |          |
|                         | %) |     |          |          | 9 |          |
|                         |    |     |          |          | ( |          |
|                         |    |     |          |          | 5 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Withdrawal of consent   | 6  |     | 5 (2%)   | **11     | * |          |
|                         | (3 |     |          | (3%)**   | * |          |
|                         | %) |     |          |          | 1 |          |
|                         |    |     |          |          | 2 |          |
|                         |    |     |          |          | ( |          |
|                         |    |     |          |          | 6 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Lack of                 | 6  |     | 5 (2%)   | **11     | * |          |
| efficacy/progression of | (3 |     |          | (3%)**   | * |          |
| study disease           | %) |     |          |          | 2 |          |
|                         |    |     |          |          | 0 |          |
|                         |    |     |          |          | ( |          |
|                         |    |     |          |          | 1 |          |
|                         |    |     |          |          | 0 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Administrative reasons  | 3  |     | 0 (0%)   | 3 (1%)   | 2 |          |
|                         | (1 |     |          |          | ( |          |
|                         | %) |     |          |          | 1 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Lost to follow-up       | 3  |     | 2 (1%)   | 3 (1%)   | 2 |          |
|                         | (1 |     |          |          | ( |          |
|                         | %) |     |          |          | 1 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Protocol violation      | 1  |     | 2 (1%)   | 3 (1%)   | 0 |          |
|                         | (\ |     |          |          | ( |          |
|                         | <1 |     |          |          | 0 |          |
|                         | %) |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Death                   | 0  |     | 1 (\<1%) | 1 (\<1%) | 0 |          |
|                         | (0 |     |          |          | ( |          |
|                         | %) |     |          |          | 0 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| # Comp                  | *  |     | **159    | **327    | * |          |
| leted study (52 weeks)  | *1 |     | (77%)**  | (78%)**  | * |          |
|                         | 68 |     |          |          | 1 |          |
|                         | (  |     |          |          | 4 |          |
|                         | 79 |     |          |          | 0 |          |
|                         | %) |     |          |          | ( |          |
|                         | ** |     |          |          | 7 |          |
|                         |    |     |          |          | 0 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| **Withdrew early**      | ** |     | **48     | **92     | * |          |
|                         | 44 |     | (23%)**  | (22%)**  | * |          |
|                         | (  |     |          |          | 6 |          |
|                         | 21 |     |          |          | 0 |          |
|                         | %) |     |          |          | ( |          |
|                         | ** |     |          |          | 3 |          |
|                         |    |     |          |          | 0 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
|                         |    |     |          |          | * |          |
|                         |    |     |          |          | * |          |
+-------------------------+----+-----+----------+----------+---+----------+
| **Withdrawals from      |    |     |          |          |   |          |
| study:**                |    |     |          |          |   |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Adverse event           | 16 |     | 26 (13%) | 42 (10%) | 1 |          |
|                         | (  |     |          |          | 3 |          |
|                         | 8  |     |          |          | ( |          |
|                         | %) |     |          |          | 7 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Withdrawal of consent   | 11 |     | 8 (4%)   | 19 (5%)  | 1 |          |
|                         | (5 |     |          |          | 5 |          |
|                         | %) |     |          |          | ( |          |
|                         |    |     |          |          | 8 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Lack of                 | 6  |     | 6 (3%)   | 12 (3%)  | 2 |          |
| efficacy/progression of | (3 |     |          |          | 3 |          |
| study disease           | %) |     |          |          | ( |          |
|                         |    |     |          |          | 1 |          |
|                         |    |     |          |          | 2 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Administrative reasons  | 5  |     | 3 (1%)   | 8 (2%)   | 7 |          |
|                         | (2 |     |          |          | ( |          |
|                         | %) |     |          |          | 4 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Lost to follow-up       | 3  |     | 2 (1%)   | 5 (1%)   | 2 |          |
|                         | (1 |     |          |          | ( |          |
|                         | %) |     |          |          | 1 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Protocol violation      | 3  |     | 2 (1%)   | 5 (1%)   | 0 |          |
|                         | (1 |     |          |          | ( |          |
|                         | %) |     |          |          | 0 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+
| Death                   | 0  |     | 1 (1%)   | 1 (0%)   | 0 |          |
|                         | (0 |     |          |          | ( |          |
|                         | %) |     |          |          | 0 |          |
|                         |    |     |          |          | % |          |
|                         |    |     |          |          | ) |          |
+-------------------------+----+-----+----------+----------+---+----------+

The demographic characteristics by randomized treatment group for all
patients who entered the study demonstrated that the majority were
Caucasians and three-quarters were females with a median age of 56
years, similar to other RA clinical trials. The demographic
characteristics in the various groups were comparable at baseline.
Participants manifested long-standing disease (medians 11 years) and
active rheumatoid arthritis, as manifested by high mean TJCs (means 28)
and SJCs (means all approximately 20 ) Over 75% of participants were RF
positive. Mean baseline total Sharp scores were \>66 and the disability
index of HAQ was approximately 1.4. (Table 13 and ).

Table 13 : Study DE019 : Demographic Characteristics

+-------------------------+----------+----------+----------+---+----------+
| #  T                    | Ad       |          |          |   |          |
| reatment {#treatment-2} | alimumab |          |          |   |          |
|                         |          |          |          |   |          |
| #  N = 619              |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
|                         | 20 mg    | 40 mg    | All      | P |          |
|                         |          |          |          | l |          |
|                         | Weekly   | Q2W      | Ad       | a |          |
|                         |          |          | alimumab | c |          |
|                         | N=212    | N=207    |          | e |          |
|                         |          |          | N=419    | b |          |
|                         |          |          |          | o |          |
|                         |          |          |          |   |          |
|                         |          |          |          | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | 0 |          |
+-------------------------+----------+----------+----------+---+----------+
| **Demographics**        |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Age (years) mean        | **57.3** | **56.1** | **56.7** | * |          |
|                         |          |          |          | * |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Gender (female %)       | **76**   | **76**   | **76**   | * |          |
|                         |          |          |          | * |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Weight (Kg) mean        | 79.0     | 77.4     | 78.2     | 8 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 1 |          |
+-------------------------+----------+----------+----------+---+----------+
| Height (cm) mean        | 166      | 165      | 165      | 1 |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | 6 |          |
+-------------------------+----------+----------+----------+---+----------+
| Race (%)                |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Caucasian               | **85**   | **84**   | **85**   | * |          |
|                         |          |          |          | * |          |
|                         |          |          |          | 8 |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Hispanic                | 7        | 6        | 6        | 8 |          |
+-------------------------+----------+----------+----------+---+----------+
| Black                   | 6        | 7        | 6        | 7 |          |
+-------------------------+----------+----------+----------+---+----------+
| Asian                   | 1        | 2        | 2        | 1 |          |
+-------------------------+----------+----------+----------+---+----------+
| Other                   | 1        | 1        | 1        | 2 |          |
+-------------------------+----------+----------+----------+---+----------+

Table 14 : Study DE019 : Disease Activity Characteristics at Baseline

+-------------------------+----------+----------+----------+---+----------+
| #  T                    | Ad       |          |          |   |          |
| reatment {#treatment-3} | alimumab |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
|                         | 20 mg    | 40 mg    | All      | P |          |
|                         |          |          |          | l |          |
|                         | Weekly   | Q2W      | Ad       | a |          |
|                         |          |          | alimumab | c |          |
|                         | N=212    | N=207    |          | e |          |
|                         |          |          | N=419    | b |          |
|                         |          |          |          | o |          |
|                         |          |          |          |   |          |
|                         |          |          |          | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | 0 |          |
+-------------------------+----------+----------+----------+---+----------+
| # Completed study       | 168      | 159      | 327      | 1 |          |
|                         | (79%)    | (77%)    | (78%)    | 4 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| Duration of RA          | **11**   | **11**   | **11**   | * |          |
| (years) - mean          |          |          |          | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Tender joint count -    | **28**   | **28**   | **28**   | * |          |
| mean                    |          |          |          | * |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | 8 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Swollen joint count -   | **20**   | **19**   | **20**   | * |          |
| mean                    |          |          |          | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Total Sharp score -     | **66.4** | **72.1** | **69.2** | * |          |
| mean                    |          |          |          | * |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 4 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Erosion score - mean    | 36.7     | 41.4     | 39.0     | 3 |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 2 |          |
+-------------------------+----------+----------+----------+---+----------+
| JS Narrowing score -    | 29.7     | 30.7     | 30.2     | 2 |          |
| mean                    |          |          |          | 9 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 2 |          |
+-------------------------+----------+----------+----------+---+----------+
| RF positive -- number   | **165    | **158    | **323    | * |          |
| (%)                     | (78%)**  | (76%)**  | (77%)**  | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 8 |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| RF levels - mean        | 309      | 273      | 291      | 4 |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | 7 |          |
+-------------------------+----------+----------+----------+---+----------+
| Disability index of     | **1.44** | **1.45** | **1.44** | * |          |
| HAQ-mean                |          |          |          | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 4 |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Duration of morning     | 114      | 111      | 113      | 1 |          |
| stiffness               |          |          |          | 1 |          |
|                         |          |          |          | 2 |          |
| minutes - mean          |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+

Previous DMARD therapy was comparable at baseline. The median total
weekly dose of MTX was 15 mg/kg for both adalimumab-treated patients and
placebo-treated patients and two-thirds of both groups received their
medication via the oral route and one-third by the parenteral route
(Table 15).

Table 15 : Study DE019 :Previous DMARD Therapy for Rheumatoid Arthritis

+-------------------------+----------+----------+----------+---+----------+
| #  T                    | Ad       |          |          |   |          |
| reatment {#treatment-4} | alimumab |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
|                         | 20 mg    | 40 mg    | All      | P |          |
|                         |          |          |          | l |          |
|                         | Weekly   | Q2W      | Ad       | a |          |
|                         |          |          | alimumab | c |          |
|                         | N=212    | N=207    |          | e |          |
|                         |          |          | N=419    | b |          |
|                         |          |          |          | o |          |
|                         |          |          |          |   |          |
|                         |          |          |          | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | 0 |          |
+-------------------------+----------+----------+----------+---+----------+
| # Completed study       | 168      | 159      | 327      | 1 |          |
|                         | (79%)    | (77%)    | (78%)    | 4 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| # MTX Administration    |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Route %                 |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Oral/ Parenteral        | 68/33    | 66/34    | 67/33    | 6 |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | / |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | 1 |          |
+-------------------------+----------+----------+----------+---+----------+
| Total weekly dose -     | 16.3     | 16.7     | 16.5     | 1 |          |
| mg/kg                   |          |          |          | 6 |          |
|                         |          |          |          | . |          |
| (mean)                  |          |          |          | 7 |          |
+-------------------------+----------+----------+----------+---+----------+

Eighty percent of patients enrolled in this trial contributed to the
Week 24 evaluation of the ACR20. Over 90% of all study patients
contributed to the Week 52 evaluation of decreased radiographic
progression, and approximately 75% of all study patients contributed to
the Week 52 Disability Index (HAQ) evaluation. Assessment of the data
contributing to the efficacy primary endpoints is shown in (Table 16).
More patients in the placebo-treated group (30%) withdrew from the trial
than patients in the adalimumab-treatment groups (22%).

Table 16 : Study DE019 : Patients With Data Contributing To The Efficacy
Assessments (Primary Endpoints)

+-------------------------+----------+----------+----------+---+----------+
| #  T                    | Ad       |          |          |   |          |
| reatment {#treatment-5} | alimumab |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
|                         | 20 mg    | 40 mg    | All      | P |          |
|                         |          |          |          | l |          |
|                         | Weekly   | Q2W      | Ad       | a |          |
|                         |          |          | alimumab | c |          |
|                         | N=212    | N=207    |          | e |          |
|                         |          |          | N=419    | b |          |
|                         |          |          |          | o |          |
|                         |          |          |          |   |          |
|                         |          |          |          | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | 0 |          |
+-------------------------+----------+----------+----------+---+----------+
| # Com                   | 168      | 159      | 327      | 1 |          |
| pleted study (52 weeks) | (79%)    | (77%)    | (78%)    | 4 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| **Withdrew early**      | 44 (21%) | 48 (23%) | 92 (22%) | 6 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| ACR 20 at week 24       | **181    | **17     | **354    | * |          |
|                         | (85%)**  | 3(84%)** | (84%)**  | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 8 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| #                       |          |          |          |   |          |
| Radiographic regression |          |          |          |   |          |
|                         |          |          |          |   |          |
| # Sh                    |          |          |          |   |          |
| arp X-ray score changes |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Baseline enrollment     | N = 201  | N= 194   | N = 395  | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 8 |          |
|                         |          |          |          | 4 |          |
+-------------------------+----------+----------+----------+---+----------+
| Scored at week 24       | **196    | **183    | **379    | * |          |
|                         | (98%)**  | (94%)**  | (96%)**  | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Scored at week 52       | **196    | **183    | **379    | * |          |
|                         | (98%)**  | (94%)**  | (96%)**  | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| **Disability Index (HAQ |          |          |          |   |          |
| change)**               |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Baseline enrollment     | N = 212  | N = 206  | N =418   | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | 9 |          |
+-------------------------+----------+----------+----------+---+----------+
| Observed score at week  | **168    | **160    | **328    | * |          |
| 52                      | (79%)**  | (78%)**  | (78%)**  | * |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 4 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+

> **C. Efficacy Analyses**

1.  **Primary Efficacy Endpoints**

The primary efficacy endpoints were 1) ACR20 response at Week 24, 2)
change in modified total Sharp x-ray score at Week 52, and 3) change in
disability index (HAQ) at Week 52 (Table 17). Statistically significant
changes are demonstrated for all three primary efficacy endpoints.

Table 17 : Study DE019 : Primary Efficacy Assessments

+-------------------------+----------+----------+----------+----------+
| #  T                    | Ad       |          |          |          |
| reatment {#treatment-6} | alimumab |          |          |          |
+-------------------------+----------+----------+----------+----------+
|                         | 20 mg    | 40 mg    | All      | Placebo  |
|                         |          |          |          |          |
|                         | Weekly   | Q2W      | Ad       | N=200    |
|                         |          |          | alimumab |          |
|                         | N=212    | N=207    |          |          |
|                         |          |          | N=419    |          |
+-------------------------+----------+----------+----------+----------+
| # Completed study N =   | 168      | 159      | 327      | 140      |
|                         | (79%)    | (77%)    | (78%)    | (70%)    |
+-------------------------+----------+----------+----------+----------+
| Primary Efficacy        |          |          |          |          |
| Assessments             |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| ACR20 Response at week  | **129    | **131(   | **260    | **59     |
| 24                      | (        | 63%)\*** | (62%)**  | (30%)**  |
|                         | 61%)\*** |          |          |          |
+-------------------------+----------+----------+----------+----------+
| **Radiographic          |          |          |          |          |
| progression -**         |          |          |          |          |
|                         |          |          |          |          |
| **Change in modified    |          |          |          |          |
| Sharp**                 |          |          |          |          |
|                         |          |          |          |          |
| **X-ray score           |          |          |          |          |
| (erosions)**            |          |          |          |          |
|                         |          |          |          |          |
| **at week 52**          |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| N = at Week 52/Baseline | 196/201  | 183/194  | 379/395  | 172/184  |
+-------------------------+----------+----------+----------+----------+
| Baseline                |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| Mean [+]{.underline} SD | 66       | 72       |          | 66       |
|                         | [+]{.un  | [+]{.un  |          | [+]{.un  |
|                         | derline} | derline} |          | derline} |
|                         | 56       | 60       |          | 47       |
+-------------------------+----------+----------+----------+----------+
| Change at Week 52       |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| Mean [+]{.underline} SD | **0.8    | **0.1    |          | **2.7    |
|                         | [+]{.un  | [+]{.un  |          | [+]{.un  |
|                         | derline} | derline} |          | derline} |
|                         | 4.9 \*** | 4.8 \*** |          | 6.8**    |
+-------------------------+----------+----------+----------+----------+
| # Disa                  |          |          |          |          |
| bility Index of the HAQ |          |          |          |          |
|                         |          |          |          |          |
| **at week 52**          |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| Baseline N =            | 212      | 206      | 418      | 199      |
+-------------------------+----------+----------+----------+----------+
| Mean [+]{.underline} SD | 1.44     | 1.45     |          | 1.48     |
|                         | [+]{.un  | [+]{.un  |          | [+]{.un  |
|                         | derline} | derline} |          | derline} |
|                         | 0.64     | 0.63     |          | 0.59     |
+-------------------------+----------+----------+----------+----------+
| Week 52 N =             | 168      | 160      | 328      | 140      |
+-------------------------+----------+----------+----------+----------+
| Change at week 52       | *        | *        |          | *        |
|                         | *-0.69** | *-0.64** |          | *-0.34** |
| [+]{.underline} SD      |          |          |          |          |
|                         | *        | *        |          | *        |
|                         | *[+]{.un | *[+]{.un |          | *[+]{.un |
|                         | derline} | derline} |          | derline} |
|                         | 0.55\*** | 0.57\*** |          | 0.54**   |
+-------------------------+----------+----------+----------+----------+
| Additional Efficacy     |          |          |          |          |
| Assessment              |          |          |          |          |
+-------------------------+----------+----------+----------+----------+
| ACR20 Response at week  | **116    | **122    | **238    | **48     |
| 52                      | (        | (        | (57%)**  | (24%)**  |
|                         | 55%)\*** | 59%)\*** |          |          |
+-------------------------+----------+----------+----------+----------+

\* Statistically significantly different from placebo (p[\<]{.underline}
0.001)

**a. ACR20 Response at Week 24**

An overall comparison of the change in ACR20 from baseline after 24
weeks of treatment revealed a statistically significant difference
(p[\<]{.underline} 0.001) in each adalimumab treatment group (20 mg
weekly \[61%\] and 40 mg q2w \[63%\]) compared to placebo \[30%\] (Table
17). The magnitude of the response at Week 24 was comparable between the
20 mg weekly and the 40 mg q2w treatments. Adalimumab-treated patients
demonstrated statistically significant changes in all components of the
ACR20 compared to placebo-treated patients (Table 18).

Table 18: Study DE019 :Components of ACR 20 Response Index (Percentage
Change at Week 24 Compared to Baseline ^a^)

^\*^ Comparison versus placebo (2-sided) p ≤ 0.05.

^\*\*^ Comparison versus placebo (2-sided) p ≤ 0.01.

^\*\*\*^ Comparison versus placebo (2-sided) p ≤ 0.001.

^a^ Negative values indicate worsening

^o^ Observed values; non-responders imputation; comparisons vs placebo
by Pearson's chi-square test

^c^ LOCF; ; Median percentage improvement -comparisons vs placebo by
ANCOVA with factor treatment group and baseline value as covariate
comparisons versus placebo (2-sided)

Evaluation of time to onset of ACR20 response by treatment groups
demonstrates that the onset of action of adalimumab occurs as early as
Week 2 with both dosages (Figure 9), and the majority of the
adalimumab-associated ACR20 responses occur within the first eight
weeks. Additionally, if an adalimumab treatment response is not observed
by Week 20, the data suggest that an ACR20 response is unlikely to
occur.

Figure 9 : Study DE019: Time to First ACR20 Response By Treatment Group

![](media/image13.wmf)

Overall, the adalimumab treatment groups had a higher response rate at
each time point compared to placebo. Separation between adalimumab- and
placebo-treated patients occurs as early as Week 2, is established by
Week 4, and is maintained through Week 52 (Figure 10).

Figure 10 : Study DE019 : Percentage ACR20 Responders by Weeks
![](media/image14.png){width="5.906944444444444in"
height="4.436805555555556in"}

Evaluation of the maintenance of the ACR20 response at Week 52 (a
secondary efficacy end-point) for adalimumab-treated patients who were
responders at week 24, reveals that approximately 85% of early
responders maintained their response through Week 52 compared to 63% for
placebo-treated patients (Table 19).

Table 19 : Study DE019 : Maintenance of ACR20 Response at Week 52 For
Patients Who Were Responders At Week 24 By Treatment Group

+------------------------------+---------------+------------+----------+
|                              | *             |            |          |
|                              | *Responders** |            |          |
+------------------------------+---------------+------------+----------+
|                              | *             |            |          |
|                              | *Adalimumab** |            |          |
+------------------------------+---------------+------------+----------+
|                              | **20 mg       | **40 mg    | **P      |
|                              | weekly**      | q2w**      | lacebo** |
+------------------------------+---------------+------------+----------+
|                              | **(N=212)**   | *          | **(      |
|                              |               | *(N=207)** | N=200)** |
+------------------------------+---------------+------------+----------+
|                              | **N (%)**     | **N (%)**  | **N      |
|                              |               |            | (%)**    |
+------------------------------+---------------+------------+----------+
| **ACR20 Response at Week 24  |               |            |          |
| (Based on all randomized     |               |            |          |
| patients)**                  |               |            |          |
+------------------------------+---------------+------------+----------+
|                              | **129 (61%)** | **         | **59     |
|                              |               | 131(63%)** | (30%)**  |
+------------------------------+---------------+------------+----------+
| **ACR20 Response at Week 52  |               |            |          |
| (Based on all randomized     |               |            |          |
| patients)**                  |               |            |          |
+------------------------------+---------------+------------+----------+
| #  Total                     | 116 (55%)     | 122 (59%)  | 48 (25%) |
+------------------------------+---------------+------------+----------+
| #                            | **107 (51%)** | **117      | **37     |
| #### Maintained from Week 24 |               | (57%)**    | (19%)**  |
+------------------------------+---------------+------------+----------+
| Not maintained               | 9 (4%)        | 5 (2%)     | 11 (6%)  |
|                              |               |            |          |
| from Week 24                 |               |            |          |
+------------------------------+---------------+------------+----------+
| **Percentage of Responders   | **107/129**   | *          | *        |
| Maintained from Week 24**    |               | *117/131** | *37/59** |
|                              | **(83%)**     |            |          |
| **Through Week 52**          |               | **(89%)**  | *        |
|                              |               |            | *(63%)** |
+------------------------------+---------------+------------+----------+

The percentage of ACR20 responses by treatment subsets among 40 mg q2w
adalimumab-treated patients at Week 24 was uniformly greater than among
placebo-treated patients with a few exceptions, i.e. among Blacks and
Hispanics. Among the adequate and well-controlled groups, the ACR20
response for Blacks at Week 24 (36%, 11/31) resembled that for placebo
(34%, 11/32). However, ACR20 responses among Blacks were higher than for
placebo at six time-points earlier than Week 24 (Week 2 \[39% vs. 13%\],
Week 4 \[42% vs. 19%\], Week 8 \[52% vs. 28%\], Week 12 \[45% vs. 25%\],
Week 16 \[48% vs. 31%\], and Week 20 \[39% vs. 31%\]). In addition,
comparison of the change in TSS (radiologic progression) between
adalimumab- and placebo-treated patients revealed the highest rate of
progression among Black placebo-treated patients (7.7u/yr) and a
markedly reduced rate of progression among Black adalimumab-treated
patients (0.4 u/yr) \[Table 22\]. Therefore, the data indicate that
Black patients did have a response to adalimumab treatment. Patients
subsetted based on weight, RF positivity, and corticosteroid use had
similar responses to adalimumab (approximately 60%) as the study
population as a whole (Table 20).

Table 20 : Study DE019 : ACR20 Responders at Week 24 by Treatment
Subsets

+----------------------------+---------+---------+---------+---------+
|                            | **Adali |         | **Pl    |         |
|                            | mumab** |         | acebo** |         |
|                            |         |         |         |         |
|                            | **40 mg |         |         |         |
|                            | Q2w**   |         |         |         |
+----------------------------+---------+---------+---------+---------+
|                            | **N**   | **%**   | **N**   | **%**   |
+----------------------------+---------+---------+---------+---------+
| ## Males                   | 35      | **71**  | 18      | **33**  |
+----------------------------+---------+---------+---------+---------+
| **Females**                | 96      | **61**  | 41      | **28**  |
+----------------------------+---------+---------+---------+---------+
| **Age**                    |         |         |         |         |
+----------------------------+---------+---------+---------+---------+
| **\< 65 years**            | 93      | **66**  | 48      | **31**  |
+----------------------------+---------+---------+---------+---------+
| **≥ 65 years**             | 42      | **65**  | 13      | **29**  |
+----------------------------+---------+---------+---------+---------+
| **Race**                   |         |         |         |         |
+----------------------------+---------+---------+---------+---------+
| **White**                  | 111     | **64**  | 39      | **24**  |
+----------------------------+---------+---------+---------+---------+
| **Black**                  | 5       | **36**  | 5       | **39**  |
+----------------------------+---------+---------+---------+---------+
| **Asian**                  | 4       | **80**  | 1       | **50**  |
+----------------------------+---------+---------+---------+---------+
| **Hispanic**               | 3       | **23**  | 6       | **40**  |
+----------------------------+---------+---------+---------+---------+
| **Other**                  | 1       | **50**  | 1       | **25**  |
+----------------------------+---------+---------+---------+---------+
| **Weight**                 |         |         |         |         |
+----------------------------+---------+---------+---------+---------+
| **≤ 70 kg**                | 56      | **62**  | 14      | **18**  |
+----------------------------+---------+---------+---------+---------+
| **≥ 70 kg**                | 75      | **64**  | 45      | **37**  |
+----------------------------+---------+---------+---------+---------+
| **RF positive**            | 110     | **66**  | 54      | **30**  |
+----------------------------+---------+---------+---------+---------+
| **RF negative**            | 26      | **67**  | 7       | **33**  |
+----------------------------+---------+---------+---------+---------+
| **Corticosteroid use +**   | 56      | **62**  | 31      | **31**  |
+----------------------------+---------+---------+---------+---------+

**b. Modified Total Sharp X-ray Score Changes at Week 52**

The rate of radiographic progression was evaluated by calculating the
change in modified total Sharp x-ray scores (TSS)(relative to baseline)
at Weeks 24 and 52. Missing data were imputed by linear extrapolation to
week 52. An overall comparison of the change from baseline in modified
total Sharp x-ray scores to Week 52 revealed a statistically significant
difference (p ≤ 0.001) across the treatment groups, and permitted
pair-wise comparisons. Significance testing was to be done following the
closure principle. The difference among all treatment groups was to be
assessed using analysis of covariance (ANCOVA) with the baseline value
as the covariate. Comparisons rates were performed using Pearson's
*x*^2^ test. The magnitude of the change associated with each of the
adalimumab treatment groups was smaller and was statistically
significantly different (p ≤ 0.001 for both) from placebo (Table 21)
indicating that adalimumab use was associated with a reduced rate of
progression of structural damage.

Observed and LOCF (use of linear extrapolation to impute missing data)
data demonstrated similar results. Similar results were observed when
the data were analyzed using the per protocol set of patients. An
overall comparison of the change from baseline in modified total Sharp
x-ray scores to Week 52 for the per-protocol set revealed a
statistically significant difference (p≤0.001) across the treatment
groups, and permitted pair-wise comparisons. The magnitude of the change
associated with each of the adalimumab treatment groups was smaller and
was statistically significantly different (p ≤ 0.001 for both) from
placebo. The mean modified total Sharp score for the proposed adalimumab
dose of 40 mg q2w at Week 52 was 0.1 compared to 0.8 for 20 mg qw and
2.7 for the placebo-treated patients.

Normality was evaluated by applying the Shapiro-Wilk test procedure to
the residuals from the parametric model. The resulting p-value was ≤
0.05 indicating the normality assumption was violated. Therefore, the
final analysis was performed following a non-parametric approach,
ranking the results prior to fitting the model. Missing values were
imputed using linear extrapolation from baseline and the last
during-study evaluation.

Table 21 : Study DE019 : Modified Total Sharp X-Ray Score Changes
(Extrapolated) At Weeks 24 and 52 By Treatment Group (full set analysis)

![](media/image15.png){width="8.552777777777777in"
height="1.4277777777777778in"}

^a^ Statistically significantly different from placebo (p ≤ 0.01) based
on median values.

^b^ Statistically significantly different from placebo (p ≤ 0.01) based
on median values

Modified total Sharp x-ray score changes are presented by subgroups in
Table 22. Comparison of the changes between adalimumab-treated patients
and placebo-treated patients demonstrates a smaller increase in modified
total Sharp x-ray scores with adalimumab compared to placebo in each of
the subgroup analyses with the exception of patients \>65 years of age.
Among patients \> 65 years of age receiving 20 mg weekly, the 12-month
change in TSS was similar to placebo (2.7 vs. 3.2 u/yr). However, in the
group receiving 40 mg q2w, the 12-month change in TSS was reduced
compared to placebo (1.6 vs. 3.2 u/yr).

Of note, the largest increase in radiographic progression occurred among
Blacks taking placebo. However, the rate of progression was reduced to a
similar level among Black patients receiving adalimumab as for other
groups. Rheumatoid factor positivity or negativity did not seem to
influence the effect of adalimumab on radiographic progression.

Table 22: Study DE019 : Modified Sharp X-Ray Score (Observed) Changes At
Week 52 By Age, Gender, Body Weight, Race, and RF Status

+-------------------------+----------+----------+----------+---+----------+
| #  T                    | Ad       |          |          |   |          |
| reatment {#treatment-7} | alimumab |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
|                         | 20 mg    | 40 mg    | All      | P |          |
|                         |          |          |          | l |          |
|                         | Weekly   | Q2W      | Ad       | a |          |
|                         |          |          | alimumab | c |          |
|                         | N=212    | N=207    |          | e |          |
|                         |          |          | N=419    | b |          |
|                         |          |          |          | o |          |
|                         |          |          |          |   |          |
|                         |          |          |          | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | 0 |          |
+-------------------------+----------+----------+----------+---+----------+
| # Completed study       | 168      | 159      | 327      | 1 |          |
|                         | (79%)    | (77%)    | (78%)    | 4 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| **Subgroup at Week 52** | N / Mean |          |          |   |          |
|                         | [+]{.un  |          |          |   |          |
|                         | derline} |          |          |   |          |
|                         | SD       |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Age                     |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| \< 65 years             | **138**  | **116**  | 254      | * |          |
|                         |          |          |          | * |          |
|                         | **0.3    | **-0.5   |          | 1 |          |
|                         | [+]{.un  | [+]{.un  |          | 2 |          |
|                         | derline} | derline} |          | 8 |          |
|                         | 2.6**    | 4.8**    |          | * |          |
|                         |          |          |          | * |          |
|                         |          |          |          |   |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| \> 65 years             | **45**   | **49**   |          | * |          |
|                         |          |          |          | * |          |
|                         | **2.7    | **1.6    |          | 3 |          |
|                         | [+]{.un  | [+]{.un  |          | 3 |          |
|                         | derline} | derline} |          | * |          |
|                         | 8.8**    | 4.8**    |          | * |          |
|                         |          |          |          |   |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | * |          |
|                         |          |          |          | * |          |
+-------------------------+----------+----------+----------+---+----------+
| Gender (female) N=      | 138      | 127      | 265      | 1 |          |
|                         |          |          |          | 1 |          |
| Change at week 52       | 1.0      | 0.3      |          | 6 |          |
|                         | [+]{.un  | [+]{.un  |          |   |          |
|                         | derline} | derline} |          | 2 |          |
|                         | 4.9      | 4.7      |          | . |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 4 |          |
+-------------------------+----------+----------+----------+---+----------+
| Body Weight             |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| [\<]{.underline} 70 Kg  | 62       | 69       | 131      | 5 |          |
| at Baseline N=          |          |          |          | 9 |          |
|                         | 0.8      | 0.2      |          |   |          |
| Change at 52 weeks      | [+]{.un  | [+]{.un  |          | 3 |          |
|                         | derline} | derline} |          | . |          |
|                         | 2.3      | 6.0      |          | 8 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 4 |          |
+-------------------------+----------+----------+----------+---+----------+
| [\>]{.underline} 70 Kg  | 121      | 96       | 217      | 1 |          |
| at Baseline N=          |          |          |          | 0 |          |
|                         | 1.0      | 0.       |          | 2 |          |
| Change at 52 weeks      | [+]{.un  | 1[+]{.un |          |   |          |
|                         | derline} | derline} |          | 2 |          |
|                         | 5.9      | 3.9      |          | . |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 9 |          |
+-------------------------+----------+----------+----------+---+----------+
| Race (%)                |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Caucasian               | 156      | 143      | 299      | 1 |          |
|                         |          |          |          | 3 |          |
|                         | 1.0      | 0.1      |          | 8 |          |
|                         | [+]{.un  | [+]{.un  |          |   |          |
|                         | derline} | derline} |          | 2 |          |
|                         | 5.4      | 5.1      |          | . |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 9 |          |
+-------------------------+----------+----------+----------+---+----------+
| Hispanic                | 11       | 6        | 17       | 1 |          |
|                         |          |          |          | 0 |          |
|                         | 0.0      | 0.0      |          |   |          |
|                         | [+]{.un  | [+]{.un  |          | 0 |          |
|                         | derline} | derline} |          | . |          |
|                         | 1.9      | 0.8      |          | 9 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 4 |          |
+-------------------------+----------+----------+----------+---+----------+
| Black                   | 11       | 11       | 22       | 8 |          |
|                         |          |          |          |   |          |
|                         | 0.7      | 0.4      |          | 7 |          |
|                         | [+]{.un  | [+]{.un  |          | . |          |
|                         | derline} | derline} |          | 7 |          |
|                         | 1.6      | 4.0      |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 6 |          |
+-------------------------+----------+----------+----------+---+----------+
| Asian                   | 2        | 4        | 6        | 2 |          |
|                         |          |          |          |   |          |
|                         | 1.8      | 0.3      |          | 3 |          |
|                         | [+]{.un  | [+]{.un  |          | . |          |
|                         | derline} | derline} |          | 8 |          |
|                         | 1.1      | 0.3      |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 3 |          |
+-------------------------+----------+----------+----------+---+----------+
| Other                   | 3        | 1        | 4        | 3 |          |
|                         |          |          |          |   |          |
|                         | 0.0      | -1.0     |          | 3 |          |
|                         | [+]{.un  |          |          | . |          |
|                         | derline} |          |          | 5 |          |
|                         | 0.0      |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 4 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 1 |          |
+-------------------------+----------+----------+----------+---+----------+
| # Rheuma                |          |          |          |   |          |
| toid Factor (positive)  |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| #  Baseline N=          | 165      | 158      | 323      | 1 |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | 5 |          |
+-------------------------+----------+----------+----------+---+----------+
| #  {#section-8}         | 68       | 77.6     |          | 6 |          |
|                         | [+]{.un  | [+]{.un  |          | 8 |          |
|                         | derline} | derline} |          | . |          |
|                         | 55.6     | 61.3     |          | 5 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 4 |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 5 |          |
+-------------------------+----------+----------+----------+---+----------+
| #  Change at Week 52 N= | 149      | 135      | 282      | 1 |          |
|                         |          |          |          | 4 |          |
|                         |          |          |          | 5 |          |
+-------------------------+----------+----------+----------+---+----------+
| #  {#section-9}         | 0.9      | 0.0      |          | 2 |          |
|                         | [+]{.un  | [+]{.un  |          | . |          |
|                         | derline} | derline} |          | 7 |          |
|                         | 5.2      | 5.3      |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 4 |          |
+-------------------------+----------+----------+----------+---+----------+
| # Rheum                 |          |          |          |   |          |
| atoid Factor (negative) |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| #  Baseline N=          | 36       | 36       | 72       | 1 |          |
|                         |          |          |          | 9 |          |
+-------------------------+----------+----------+----------+---+----------+
| #  {#section-10}        | 58.9     | 48.0     |          | 4 |          |
|                         | [+]{.un  | [+]{.un  |          | 8 |          |
|                         | derline} | derline} |          | . |          |
|                         | 59.6     | 52.6     |          | 2 |          |
|                         |          |          |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 4 |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 3 |          |
+-------------------------+----------+----------+----------+---+----------+
| #  Change at Week 52 N= | 34       | 30       | 64       | 1 |          |
|                         |          |          |          | 6 |          |
+-------------------------+----------+----------+----------+---+----------+
|                         | 1.1      | 0.5      |          | 3 |          |
|                         | [+]{.un  | [+]{.un  |          | . |          |
|                         | derline} | derline} |          | 3 |          |
|                         | 4.1      | 1.9      |          | [ |          |
|                         |          |          |          | + |          |
|                         |          |          |          | ] |          |
|                         |          |          |          | { |          |
|                         |          |          |          | . |          |
|                         |          |          |          | u |          |
|                         |          |          |          | n |          |
|                         |          |          |          | d |          |
|                         |          |          |          | e |          |
|                         |          |          |          | r |          |
|                         |          |          |          | l |          |
|                         |          |          |          | i |          |
|                         |          |          |          | n |          |
|                         |          |          |          | e |          |
|                         |          |          |          | } |          |
|                         |          |          |          | 9 |          |
|                         |          |          |          | . |          |
|                         |          |          |          | 8 |          |
+-------------------------+----------+----------+----------+---+----------+

As expected, the baseline TSSs were progressively higher in patients
with increasing duration of RA. The overall therapeutic effect of
adalimumab was similar at all stages of the disease (Table 23)

Table 23 : Study DE019 : Modified Total Sharp X-Ray Score (Observed)
Changes At Week 52 By Duration of RA

+-------------------------+----------+----------+---------+---+----------+
| #  T                    | #### Ad  |          |         |   |          |
| reatment {#treatment-8} | alimumab |          |         |   |          |
|                         |  {#adali |          |         |   |          |
|                         | mumab-4} |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
|                         | 20 mg    | 40 mg    | All     | # |          |
|                         |          |          |         | # |          |
|                         | Weekly   | Q2W      | Ada     | # |          |
|                         |          |          | limumab | # |          |
|                         | N=212    | N=207    |         |   |          |
|                         |          |          | N=419   | P |          |
|                         |          |          |         | l |          |
|                         |          |          |         | a |          |
|                         |          |          |         | c |          |
|                         |          |          |         | e |          |
|                         |          |          |         | b |          |
|                         |          |          |         | o |          |
|                         |          |          |         |   |          |
|                         |          |          |         | { |          |
|                         |          |          |         | # |          |
|                         |          |          |         | p |          |
|                         |          |          |         | l |          |
|                         |          |          |         | a |          |
|                         |          |          |         | c |          |
|                         |          |          |         | e |          |
|                         |          |          |         | b |          |
|                         |          |          |         | o |          |
|                         |          |          |         | - |          |
|                         |          |          |         | 3 |          |
|                         |          |          |         | } |          |
|                         |          |          |         |   |          |
|                         |          |          |         | N |          |
|                         |          |          |         | = |          |
|                         |          |          |         | 2 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | 0 |          |
+-------------------------+----------+----------+---------+---+----------+
| # Com                   | 168      | 159      | 327     | 1 |          |
| pleted study (52 weeks) | (79%)    | (77%)    | (78%)   | 4 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | ( |          |
|                         |          |          |         | 7 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | % |          |
|                         |          |          |         | ) |          |
+-------------------------+----------+----------+---------+---+----------+
| **Withdrew early**      | 44 (21%) | 48 (23%) | 92      | 6 |          |
|                         |          |          | (22%)   | 0 |          |
|                         |          |          |         | ( |          |
|                         |          |          |         | 3 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | % |          |
|                         |          |          |         | ) |          |
+-------------------------+----------+----------+---------+---+----------+
| **Duration of RA**      |          |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
| **0 --2 years**         |          |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Baseline N=          | 28       | 24       | 52      | 1 |          |
|                         |          |          |         | 8 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-11}        | 21.7     | 28.3     |         | 2 |          |
|                         | [+]{.un  | [+]{.un  |         | 5 |          |
|                         | derline} | derline} |         | . |          |
|                         | 14.5     | 27.4     |         | 9 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 1 |          |
|                         |          |          |         | 8 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 4 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Change at Week 52 N= | 24       | 24       | 48      | 1 |          |
|                         |          |          |         | 5 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-12}        | -0.0     | 0.4      |         | 4 |          |
|                         | [+]{.un  | [+]{.un  |         | . |          |
|                         | derline} | derline} |         | 7 |          |
|                         | 1.2      | 4.1      |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 6 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 3 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  \>2 -- 5 years       |          |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Baseline N=          | 37       | 42       | 79      | 4 |          |
|                         |          |          |         | 3 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-13}        | 44.5     | 36.3     |         | 4 |          |
|                         | [+]{.un  | [+]{.un  |         | 4 |          |
|                         | derline} | derline} |         | . |          |
|                         | 38.1     | 31.5     |         | 3 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 3 |          |
|                         |          |          |         | 7 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 1 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Change at Week 52 N= | 34       | 36       | 70      | 3 |          |
|                         |          |          |         | 8 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-14}        | 1.5      | 1.1      |         | 3 |          |
|                         | [+]{.un  | [+]{.un  |         | . |          |
|                         | derline} | derline} |         | 9 |          |
|                         | 9.1      | 2.4      |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 8 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 3 |          |
+-------------------------+----------+----------+---------+---+----------+
| \>5 -- 10 years         |          |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Baseline N=          | 48       | 42       | 90      | 4 |          |
|                         |          |          |         | 1 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-15}        | 61.3     | 51.9     |         | 5 |          |
|                         | [+]{.un  | [+]{.un  |         | 5 |          |
|                         | derline} | derline} |         | . |          |
|                         | 44.9     | 36.7     |         | 3 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 3 |          |
|                         |          |          |         | 9 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 0 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Change at Week 52 N= | 41       | 31       | 72      | 3 |          |
|                         |          |          |         | 5 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-16}        | -0.3     | -0.3     |         | 2 |          |
|                         | [+]{.un  | [+]{.un  |         | . |          |
|                         | derline} | derline} |         | 3 |          |
|                         | 3.4      | 3.9      |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 5 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 9 |          |
+-------------------------+----------+----------+---------+---+----------+
| \> 10 years             |          |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Baseline N=          | 87       | 86       | 173     | 8 |          |
|                         |          |          |         | 2 |          |
+-------------------------+----------+----------+---------+---+----------+
| #   {#section-17}       | 93.3     | 111.6    |         | 9 |          |
|                         | [+]{.un  | [+]{.un  |         | 2 |          |
|                         | derline} | derline} |         | . |          |
|                         | 63.1     | 63.9     |         | 4 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 4 |          |
|                         |          |          |         | 6 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 5 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Change at Week 52 N= | 83       | 74       | 157     | 7 |          |
|                         |          |          |         | 3 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-18}        | 1.6      | -0.3     |         | 2 |          |
|                         | [+]{.un  | [+]{.un  |         | . |          |
|                         | derline} | derline} |         | 0 |          |
|                         | 3.9      | 6.2      |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 6 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 3 |          |
+-------------------------+----------+----------+---------+---+----------+

Source of Data: Sponsor's Table 25

The magnitude of the baseline TSSs did not have any apparent influence
on the decrease in rate of progression of adalimumab-treated patients at
the proposed dose compared to placebo-treated patients (Table 24).

Table 24 : Study DE019 : Modified Total Sharp X-Ray Score (Observed)
Changes At Week 52 (Continued)

+-------------------------+----------+----------+---------+---+----------+
| #  T                    | Ad       |          |         |   |          |
| reatment {#treatment-9} | alimumab |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
|                         | 20 mg    | 40 mg    | All     | P |          |
|                         |          |          |         | l |          |
|                         | Weekly   | Q2W      | Ada     | a |          |
|                         |          |          | limumab | c |          |
|                         | N=212    | N=207    |         | e |          |
|                         |          |          | N=419   | b |          |
|                         |          |          |         | o |          |
|                         |          |          |         |   |          |
|                         |          |          |         | N |          |
|                         |          |          |         | = |          |
|                         |          |          |         | 2 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | 0 |          |
+-------------------------+----------+----------+---------+---+----------+
| # Com                   | 168      | 159      | 327     | 1 |          |
| pleted study (52 weeks) | (79%)    | (77%)    | (78%)   | 4 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | ( |          |
|                         |          |          |         | 7 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | % |          |
|                         |          |          |         | ) |          |
+-------------------------+----------+----------+---------+---+----------+
| **Withdrew early**      | 44 (21%) | 48 (23%) | 92      | 6 |          |
|                         |          |          | (22%)   | 0 |          |
|                         |          |          |         | ( |          |
|                         |          |          |         | 3 |          |
|                         |          |          |         | 0 |          |
|                         |          |          |         | % |          |
|                         |          |          |         | ) |          |
+-------------------------+----------+----------+---------+---+----------+
| **Baseline Sharp        |          |          |         |   |          |
| score**                 |          |          |         |   |          |
+-------------------------+----------+----------+---------+---+----------+
| **Baseline score \<30   | 59       | 59       | 118     | 5 |          |
| N=**                    |          |          |         | 1 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-19}        | 16.0     | 15.9     |         | 1 |          |
|                         | [+]{.un  | [+]{.un  |         | 6 |          |
|                         | derline} | derline} |         | . |          |
|                         | 7.5      | 7.0      |         | 4 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 8 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 3 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Change at Week 52 N= | 52       | 53       | 105     | 4 |          |
|                         |          |          |         | 4 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-20}        | **-0.0   | **0.5    |         | * |          |
|                         | [+]{.un  | [+]{.un  |         | * |          |
|                         | derline} | derline} |         | 1 |          |
|                         | 1.4**    | 2.9**    |         | . |          |
|                         |          |          |         | 5 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 3 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 3 |          |
|                         |          |          |         | * |          |
|                         |          |          |         | * |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Bas                  | 91       | 81       | 172     | 7 |          |
| eline score 30 -- 90 N= |          |          |         | 5 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-21}        | 55.3     | 58.7     |         | 5 |          |
|                         | [+]{.un  | [+]{.un  |         | 4 |          |
|                         | derline} | derline} |         | . |          |
|                         | 16.9     | 18.9     |         | 5 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 1 |          |
|                         |          |          |         | 6 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 5 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Change at Week 52 N= | 82       | 65       | 147     | 6 |          |
|                         |          |          |         | 8 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-22}        | **1.2    | **-0.2   |         | * |          |
|                         | [+]{.un  | [+]{.un  |         | * |          |
|                         | derline} | derline} |         | 4 |          |
|                         | 3.5**    | 5.4**    |         | . |          |
|                         |          |          |         | 1 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 7 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 6 |          |
|                         |          |          |         | * |          |
|                         |          |          |         | * |          |
+-------------------------+----------+----------+---------+---+----------+
| Baseline score \> 90 N= | 51       | 54       | 105     | 5 |          |
|                         |          |          |         | 8 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-23}        | 144.4    | 153.6    |         | 1 |          |
|                         | [+]{.un  | [+]{.un  |         | 2 |          |
|                         | derline} | derline} |         | 5 |          |
|                         | 51.6     | 47.8     |         | . |          |
|                         |          |          |         | 7 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 2 |          |
|                         |          |          |         | 8 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 2 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  Change at Week 52 N= | 49       | 47       | 96      | 4 |          |
|                         |          |          |         | 9 |          |
+-------------------------+----------+----------+---------+---+----------+
| #  {#section-24}        | **1.5    | **0.1    |         | * |          |
|                         | [+]{.un  | [+]{.un  |         | * |          |
|                         | derline} | derline} |         | 2 |          |
|                         | 8.4**    | 5.9**    |         | . |          |
|                         |          |          |         | 1 |          |
|                         |          |          |         | [ |          |
|                         |          |          |         | + |          |
|                         |          |          |         | ] |          |
|                         |          |          |         | { |          |
|                         |          |          |         | . |          |
|                         |          |          |         | u |          |
|                         |          |          |         | n |          |
|                         |          |          |         | d |          |
|                         |          |          |         | e |          |
|                         |          |          |         | r |          |
|                         |          |          |         | l |          |
|                         |          |          |         | i |          |
|                         |          |          |         | n |          |
|                         |          |          |         | e |          |
|                         |          |          |         | } |          |
|                         |          |          |         | 7 |          |
|                         |          |          |         | . |          |
|                         |          |          |         | 6 |          |
|                         |          |          |         | * |          |
|                         |          |          |         | * |          |
+-------------------------+----------+----------+---------+---+----------+

We performed analyses to determine what fraction of patients experienced
no x-ray progression. At week 24, similar proportions of
adalimumab-treated patients and placebo-treated patients manifested no
new erosions. However at Week 52, 60% of the 40 mg q2w
adalimumab-treated patients had no new erosions compared to baseline vs.
46% of placebo-treated patients (Table 25).

Table 25 : Study DE019 : Erosion Score: Patients with No New Erosions
and Lower Erosion Scores at Weeks 24 and 52 by Randomized Treatment
Group (full analysis set)

  ----------------------------- ---------------- ------- ------- ----------- ------------- --------
  **TimePoint**                 **Adalimumab**                               **Placebo**   

                                **20 mg weekly**         **40 mg                           
                                                         Q2w**                             

                                **N**            **%**   **N**   **%**       **N**         **%**

  **Patients with no new                                                                   
  erosions (=0 and \<0)**                                                                  

  **Week 24**                   117              62      108     **61**      99            **60**

  **LOCF Week 24**              119              62      119     **62**      103           **58**

  **Week 52**                   106              58^a^   102     **62**^b^   74            **46**

  **LOCF Week 52**              119              59^a^   122     **63**^c^   85            **46**

  **Patients with lower erosion                                                            
  scores (\<0)^d^**                                                                        

  **Week 24**                   59               31      65      **37**^a^   41            **25**

  **LOCF Week 24**              60               31      69      **36**^a^   41            **23**

  **Week 52**                   54               30^a^   63      **38**^c^   31            **19**

  **LOCF Week 52**              57               28^a^   72      **37**^c^   35            **19**
  ----------------------------- ---------------- ------- ------- ----------- ------------- --------

a Statistically significantly different from placebo (p ≤ 0.05).

b Statistically significantly different from placebo (p ≤ 0.01).

c Statistically significantly different from placebo (p ≤ 0.001).

d Comparison was done across three categories: \<0, 0 and \>0.

Erosion score changes were greater for placebo-treated patients than for
40 mg biweekly adalimumab-treated patients at both Week 24 and Week 52,
and changes for 20 mg weekly adalimumab-treated patients were
intermediate. LOCF data demonstrated similar results (Table 26).

Table 26 : Study DE019 : Erosion Score at Weeks 24 and Week 52 By
Randomized Treatment Group -- (full analysis set)

![](media/image16.png){width="5.995833333333334in"
height="2.3722222222222222in"}

Adalimumab-treated patients demonstrated less of an increase in JSN
scores than placebo at Weeks 24 and 52 (Table 27). The nominal p-values
for these comparisons were \<0.005.

Table 27 : Study DE019 : Joint Space Narrowing: Change in Joint Space
Narrowing and Joint Space Narrowing Scores at Weeks 24 and 52 by
Randomized Treatment Group (full analysis set)

![](media/image17.png){width="5.995138888888889in" height="3.90625in"}

Table 28 presents the changes in TSS by quartiles and the 10^th^/90^th^
percentiles. The 90^th^ percentile for changes in TSS was 3 units for
adalimumab-treated patients compared to 10 units for placebo.

Table 28: Study DE019 : Change from baseline at Week 52 in TSS\*

\--Repeat Sponsor's primary analysis with additional quartiles of
information

  -----------------------------------------------------------------------
  Group n mean std median q1 q3 p10 p90 min max

  20 MG WEEKLY 196 0.79 4.94 0 -0.5 1.08 -2.0 3 -14.5 50.5

  40 MG BIWEEKLY 183 0.09 4.77 0 -1.0 1.08 -2.5 3 -37.0 23.5

  PLACEBO 172 2.67 6.76 1 0.0 4.00 -1.0 10 -25.0 39.0
  -----------------------------------------------------------------------

\*: Patients without baseline score or one score after baseline were
excluded.

For patients without score at Week 52, their values were estimated using
linear extrapolation method.

An analysis was performed to assess whether a linear imputation method
or LOCF would be the best imputation technique for handling missing
data. Table 29 demonstrates that

similar results are seen for the 12-month change in TSS using the two
imputation techniques. This is not surprising given the small amount of
missing data in the trial.

Table 29 : Study DE019 : Comparison of Statistical Inference Conclusions
Based on Change from Baseline at Week 52 in TSS\* Using Different
Imputation Methods

+--------------------+------------------------+------------------------+
| Imputation Method  | [40 MG BIWEEKLY        | [PLACEBO               |
|                    | (n=183)]{.underline}   | (n=172)]{.underline}   |
|                    |                        |                        |
|                    | Mean SD Median         | Mean SD Median         |
+--------------------+------------------------+------------------------+
| Linear             | 0.09 4.77 0            | 2.67 6.76 1            |
| Extrapolation      |                        |                        |
|                    | 0.13 4.70 0            | 2.63 6.61 1            |
| LOCF               |                        |                        |
+--------------------+------------------------+------------------------+

\*: Patients without baseline score or one score after baseline were
excluded.

Table 30 uses data for patients who had baseline, Week 24 and Week 52
x-ray assessments, and displays the difference between the actual
Week-52 value and that obtained by imputing Week-52 values from Week-24
values using linear extrapolation or LOCF. For untreated patients,
linear extrapolation closely approximated Week-52 values (mean
difference = 0.05), while LOCF values differed markedly (mean difference
= 1.48). This analysis suggests that linear extrapolation is a more
accurate imputation technique.

Table 30 : Study DE019 : Difference Between the Real and the Imputed
Values at Week 52 in TSS\*

+--------------------+------------------------+------------------------+
| Imputation Method  | [40 MG BIWEEKLY        | [PLACEBO               |
|                    | (n=183)]{.underline}   | (n=172)]{.underline}   |
|                    |                        |                        |
|                    | Mean SD Median         | Mean SD Median         |
+--------------------+------------------------+------------------------+
| Linear             | -0.53 9.21 0           | 0.05 6.96 0            |
| Extrapolation      |                        |                        |
|                    | -0.15 5.22 0           | 1.48 5.48 0.5          |
| LOCF               |                        |                        |
+--------------------+------------------------+------------------------+

\*: Patients without complete TSS score were excluded.

Table 31 presents additional sensitivity analyses to support the
statistical findings of the primary analysis. Statistically significant
differences between adalimumab and placebo remain when worse scores
(75^th^ percentile) are imputed for missing values with adalimumab and
better scores (25^th^ percentile) for placebo (Sensitivity Analysis
III). A worse case scenario (Sensitivity Analysis IV) abrogates the
treatment effect.

Table 31 : Study DE019 : Sensitivity Analyses Total Sharp Score

#### Sensitivity Analysis I

#### Assigning the worst change (50.5) to all patients with missing values

  -----------------------------------------------------------------------
  Group n mean std median q1 q3 min max P-value\*

  20 MG WEEKLY 212 4.54 13.99 0.5 -0.5 2.00 -14.5 50.5 \<0.0001

  40 MG BIWEEKLY 207 5.93 16.79 0.0 -1.0 2.00 -37.0 50.5 \<0.0001

  PLACEBO 200 9.37 17.78 1.5 0.0 8.25 -25.0 50.5
  -----------------------------------------------------------------------

\*: Adalimumab group vs. placebo group using Wilcoxon rank sum test.

#### Sensitivity Analysis II

**Assigning the median change (0.5) to all patients with missing
values**

  -----------------------------------------------------------------------
  Group n mean std median q1 q3 min max P-value\*

  20 MG WEEKLY 212 0.76 4.75 0.5 -0.5 1.00 -14.5 50.5 \<0.0001

  40 MG BIWEEKLY 207 0.13 4.48 0.0 -1.0 1.00 -37.0 23.5 \<0.0001

  PLACEBO 200 2.37 6.31 0.5 0.0 3.25 -25.0 39.0
  -----------------------------------------------------------------------

\*: Adalimumab group vs. placebo group using Wilcoxon rank sum test.

######## Sensitivity Analysis III

**Assigning the 75^th^ percentile change (2.0) to patients with missing
values treated with Adalimumab Assigning the 25^th^ percentile change
(-.5) to patients with missing values treated with placebo**

  -----------------------------------------------------------------------
  Group n mean std median q1 q3 min max P-value\*

  20 MG WEEKLY 212 0.88 4.76 0.5 -0.5 2.00 -14.5 50.5 0.051

  40 MG BIWEEKLY 207 0.31 4.52 0.0 -1.0 2.00 -37.0 23.5 0.0054

  PLACEBO 200 2.23 6.36 0.5 -0.5 3.25 -25.0 39.0
  -----------------------------------------------------------------------

\*: Adalimumab group vs. placebo group using Wilcoxon rank sum test.

######## Sensitivity Analysis IV

> **Assigning the worst change (50.5) to patients with missing values
> treated with Adalimumab Assigning the best change (-37.0) to patients
> with missing values treated with placebo**

  -----------------------------------------------------------------------
  Group n mean std median q1 q3 min max P-value\*

  20 MG WEEKLY 212 4.54 13.99 0.5 -0.5 2.00 -14.5 50.5 0.8896

  40 MG BIWEEKLY 207 5.93 16.79 0.0 -1.0 2.00 -37.0 50.5 0.9669

  PLACEBO 200 -2.88 15.16 0.5 -0.5 3.25 -37.0 39.0
  -----------------------------------------------------------------------

\*: Adalimumab group vs. placebo group using Wilcoxon rank sum test.

> **c. Disability Index of the HAQ at Week 52**

An improvement in the disability index of the HAQ was represented by a
negative mean change from baseline (i.e., assessed decrease in disease).
After 52 weeks of treatment, both adalimumab dose groups (20 mg weekly
and 40 mg q2w) were associated with statistically significant (p ≤
0.001) improvements in observed disability index (HAQ) compared to
placebo (Table 32).

The change in disability index of the HAQ scores at Week 52 for the
adalimumab treatment groups in the per-protocol set were also
statistically significantly superior (p\<0.001) to placebo. The scores
at Week 52 were comparable between 20 mg weekly and 40 mg eow treatment
groups

Normality was evaluated by applying the Shapiro-Wilk test procedure to
the residuals from the parametric model. The resulting p-value was
\>0.05 indicating the normality assumption was not violated. The final
analysis was therefore performed following a parametric approach. ANCOVA
statistical analyses was utilized for change in modified

change in disability index of the HAQ.

Table 32 : DE019 : Disability index of the HAQ at Week 52 by Randomized
Treatment Group (full analysis set)

![](media/image18.png){width="5.997916666666667in"
height="1.3756944444444446in"}

Among adalimumab-treated patients treated with 40 mg biweekly, 60%
achieved HAQ (improvement) score reductions of [\>]{.underline} 0.22 and
46% achieved HAQ score reductions of

[\>]{.underline} 0.50 units at 52 weeks. Among placebo-treated patients
41% achieved HAQ score reductions of [\>]{.underline} 0.22 and 25%
achieved HAQ score reductions of [\>]{.underline} 0.50 units.

**2. Secondary Efficacy Endpoints**

A substantial number of adalimumab-treated patients demonstrated ACR50
responses (40%) at both Week 24 and Week 52 compared to placebo (10%)
(Table 33). \[Continuous secondary efficacy variables were to be
analyzed using ANCOVA, with baseline and treatment group as covariates.
Pearson's *x*^2^ test was to be used for discrete data\]

Table 33 : Study DE019 : ACR50 Response At Weeks 24 and 52: Number (%)
of Patients Responding By Randomized Treatment Group

+-------------------+-------------------+------------+---------------+
|                   | ###### Adalimuma  |            |               |
|                   | b {#adalimumab-5} |            |               |
+-------------------+-------------------+------------+---------------+
| **Time point**    | **20 mg weekly**  | **40 mg    | **Placebo**   |
|                   |                   | q2w**      |               |
+-------------------+-------------------+------------+---------------+
| **Week 24**       | (N=212)           | (N=207)    | (N=200)       |
+-------------------+-------------------+------------+---------------+
|                   | **87 (41) ^a^**   | **81       | **19 (10)**   |
|                   |                   | (39)^a^**  |               |
+-------------------+-------------------+------------+---------------+
| ######### Week 52 | **80 (38) ^a^**   | **86 (42)  | **19 (10)**   |
|                   |                   | ^a^**      |               |
+-------------------+-------------------+------------+---------------+

^a^ Statistically significantly different from placebo (p ≤0.001)

Over 20% of the 40 mg biweekly adalimumab-treated patients demonstrated
ACR70 responses at both Week 24 and Week 52 (Table 34).

Table 34 : Study DE019 :ACR70 Response At Weeks 24 and 52: Numbers (%)
of Patients Responding By Randomized Treatment Group

+--------------------+-------------------+------------+---------------+
|                    | **Adalimumab**    |            |               |
+--------------------+-------------------+------------+---------------+
|                    | **20 mg weekly**  | **40 mg    | **Placebo**   |
|                    |                   | q2w**      |               |
+--------------------+-------------------+------------+---------------+
| **Time point**     | (N=212)           | (N=207)    | (N=200)       |
+--------------------+-------------------+------------+---------------+
| **Week 24**        | **37 (18) ^a^**   | **43 (21)  | **5 (3)**     |
|                    |                   | ^a^**      |               |
+--------------------+-------------------+------------+---------------+
| ## Week 52         | **44 (21) ^a^**   | **48 (23)  | **9 (5)**     |
|                    |                   | ^a^**      |               |
+--------------------+-------------------+------------+---------------+

^a^ Statistically significantly different from placebo (p ≤0.001)

Source: sponsor's Table 30

A significantly greater proportion of adalimumab-treated patients than
placebo experienced a major clinical response at Week 52, a unique
achievement for a RA therapeutic agent in a 1-year study. (Table 35)

Table 35 : Study DE019 : Major Clinical Response at Week 52 by Treatment
Group

  ------------------------ ----------------- -------------- --------------
                           Adalimumab                       

                           20 mg weekly      40 mg q2w      Placebo

  **Major clinical         (N=212)           (N=207)        (N=200)
  response^a^**                                             

  **Yes**                  **20 (9.4)^b^**   **18           **3 (1.5)**
                                             (8.7)^b^**     
  ------------------------ ----------------- -------------- --------------

^a^ Defined as a continuous ACR70 over a 6 month period

^b^ Statistically significantly different from placebo (p ≤0.001)

The percentages of ACR50, ACR70 , and major clinical responses for
adalimumab, all demonstrated statistical significance.

Table 36 demonstrates the higher number and percentage of
placebo-treated patients compared to adalimumab-treated patients who
were non-responders and required additional DMARDs.

Table 36 : Study DE019 : Number of Patients Using Additional DMARDs

+-------------------------+----------+----------+----------+---+----------+
| **Enrolled in study**   | N = 619  |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| #  Tr                   | Ad       |          |          |   |          |
| eatment {#treatment-10} | alimumab |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
|                         | 20 mg    | 40 mg    | All      | P |          |
|                         |          |          |          | l |          |
|                         | Weekly   | Q2W      | Ad       | a |          |
|                         |          |          | alimumab | c |          |
|                         | N=212    | N=207    |          | e |          |
|                         |          |          | N=419    | b |          |
|                         |          |          |          | o |          |
|                         |          |          |          |   |          |
|                         |          |          |          | N |          |
|                         |          |          |          | = |          |
|                         |          |          |          | 2 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | 0 |          |
+-------------------------+----------+----------+----------+---+----------+
| # Completed study       | 168      | 159      | 327      | 1 |          |
|                         | (79%)    | (77%)    | (78%)    | 4 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 7 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| **Withdrew early**      | 44 (21%) | 48 (23%) | 92 (22%) | 6 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 3 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| **Number of patients    |          |          |          |   |          |
| using additional        |          |          |          |   |          |
| DMARDs**                |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| Week 24                 |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| ACR20 responder         | 0        | 2 (1%)   | 2 (1%)   | 1 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| ACR20 non-responder     | 6 (3%)   | 7 (3%)   | 13 (3%)  | 3 |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 6 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+
| Week 52                 |          |          |          |   |          |
+-------------------------+----------+----------+----------+---+----------+
| ACR20 responder         | 0        | 0        | 0        | 0 |          |
+-------------------------+----------+----------+----------+---+----------+
| ACR20 non-responder     | 6 (3%)   | 8 (4%)   | 14 (3%)  | 3 |          |
|                         |          |          |          | 0 |          |
|                         |          |          |          | ( |          |
|                         |          |          |          | 1 |          |
|                         |          |          |          | 5 |          |
|                         |          |          |          | % |          |
|                         |          |          |          | ) |          |
+-------------------------+----------+----------+----------+---+----------+

**3. Summary of Efficacy Data**

In this trial, there were three primary efficacy endpoints: the ACR20
response rate at Week 24 was the highest hierarchical primary efficacy
outcome, followed by comparisons of the modified total Sharp x-ray score
changes at Week 52, and the third primary efficacy endpoint was the
disability index of the HAQ change at Week 52. The ACR20 response at
Week 24 for both adalimumab-treatment groups (20 mg weekly \[61%\] and
40 mg q2w \[63%\], the proposed approval dosage) was statistically
superior to the placebo-treated group (30%). The separation between
adalimumab- and placebo-treated patients occurred as early as Week 2,
was established by Week 4, and maintained through Week 52. All subsets
of patients examined demonstrated a treatment effect of adalimumab.

Comparison of the change from baseline in modified total Sharp x-ray
scores to Week 52 revealed a statistically significant difference
between adalimumab-treatment groups and the placebo-treated group. The
smaller changes observed in patients treated with adalimumab was
consistent with a slowing of the rate of progressions of structural
damage.

The study demonstrated a greater degree of improvement in the HAQ scores
from baseline to Week 52 for both adalimumab doses compared to placebo.
While these data are consistent with an important clinical benefit, they
do not meet the criteria outlined in the guidance document for a claim
of improvement in physical function/prevention of disability.
Demonstration of sustained improvement for 2 years is required for this
claim.

**V. Study DE031 - Adalimumab Plus Stable Dose DMARD**

A. Clinical Trial Design

Study DE031 is a multicenter, randomized, double-blind,
placebo-controlled, phase III 24 week trial in which adalimumab 40 mg is
self-administered subcutaneously (sc) every other week to patients with
RA whose disease was not adequately treated with their current
anti-rheumatic therapies. The primary objective is to contrast the
safety profile of adalimumab with placebo when both are administered
with pre-existing rheumatologic care in patients with active RA. The
secondary objective is to determine and compare the efficacy of
adalimumab with placebo when both are administered with pre-existing
rheumatologic care. Efficacy is measured by ACR20 response criteria and
improvement in physical function and health-related quality of life as
measured by the HAQ and SF-36.

Patients had a confirmed diagnosis of RA (as defined by the 1987-revised
ACR criteria) for at least 3 months and were in ACR functional class I,
II, or III. Patients were inadequately treated with their current
anti-rheumatic therapies and had active RA. Doses of DMARDs, as well as
concomitant prednisone (≤10 mg daily) and NSAIDs, were required to be
stable for at least 28 days prior to screening. At the baseline visit,
patients were randomized to adalimumab or placebo (randomly assigned in
a 1:1 ratio) and this signified the start of the 24-week
placebo-controlled period. Patients were examined at Weeks 2, 4, 8, 12,
16, 20 and 24 of the study. Patients who failed to meet or maintain an
ACR20 response were allowed a single increase in dosage of their DMARD
and/or steroid therapy, treatment with another DMARD after 3 months of
study participation, or further dose adjustments following consultation
with the medical monitor. Patients who prematurely withdrew for lack of
efficacy received usual medical care. All patients who completed the
placebo-controlled period were eligible for enrollment into the open
label continuation Study DE031X .

Planned enrollment for this study was 400 patients. However, based on
changes made in Amendment B, the planned sample size was increased to
600 patients (Figure 11). Ultimately, 636 patients were analyzed, 318 in
each treatment group, the adalimumab-treatment group and the
placebo-treated group .

![](media/image19.png){width="6.375in" height="2.1666666666666665in"}

> Figure 11: Study DE031 : Study Design

This study was designed to evaluate the safety and efficacy of
adalimumab compared to a placebo control in patients with RA who were
not adequately responding to other anti-rheumatic therapies and reflect
the safety and efficacy that will be experienced post approval within
usual current clinical practice. The study design reflected standard
clinical practice, and therefore allowed adjunctive treatments and dose
adjustments. A washout period for azathioprine and cyclosporine was
chosen to decrease the potential for immunosuppression during the study.

Clinical adverse events (AEs), infections, immune reactions,
malignancies, injection site reactions, changes in physical
examinations, laboratory evaluations and vital signs were monitored.
Chest x-rays and electrocardiograms (ECG) were done at study entry; an
additional chest x-ray was performed at Week 12 in patients with
positive tuberculin purified protein derivative (PPD) skin tests.

# Eligibility consisted of RA patients with:

# Inclusion criteria -- major criteria for patients 

-   Patients were 18 years of age or older. Female patients of
    child-bearing potential had negative pregnancy test at screen.

-   ACR criteria of active RA for at least 3 months (≥ 6 swollen joints
    and ≥9 tender joints)

-   Receiving glucocorticoids equivalent to ≥10 mg of prednisone daily

-   DMARD dose was required to remain unchanged for at least 28 days

-   All males and females of reproductive potential used a reliable
    method of contraception.

#  {#section-25}

# Exclusion criteria -- major criteria for patients

-   Who had received previous treatment with total lymphoid irradiation,
    monoclonal antibodies, alkylating agents, any TNF antagonist,
    intravenous (iv) immunoglobulin or any investigational agent

-   History of cancer, lymphoproliferative disease, or positive HIV
    status.

-   History of or current acute inflammatory joint disease other than RA

-   History of unstable, persistent, or chronic medical conditions,
    infection, active tuberculosis or listeriosis, iv antibiotics within
    30 days, or oral antibiotics within 14 days prior to screening

-   Pregnant or breast-feeding.

-   History of clinically significant drug or alcohol abuse, drug abuse,
    having received intra-articular, intramuscular, or iv administration
    of corticosteroids within 4 weeks evaluation,

-   Joint surgery within 2 months prior to the screening evaluation.

-   Abnormal laboratory values: hematological, hepatic or renal

# Concomitant therapy

All concomitant therapies, including over-the-counter preparations,
taken by the patient during the study were recorded on the CRF. Patients
were allowed to continue drug therapies including antirheumatic
therapies during the study except for azathioprine and/or cyclosporine.
Patients continued to receive their pre-study dose of anti-rheumatic
therapies. Anti-rheumatic therapies permitted for use during the study
included DMARDs (hydroxychloroquine, leflunomide, methotrexate,
parenteral gold, oral gold and sulfasalazine, or any combination of
these or other DMARDs), NSAIDs and oral or intra-articular steroids.
Doses of these DMARDs as well as concomitant prednisone (≤10 mg daily)
and NSAIDs must have been stable for at least 28 days prior to
screening. All efforts were made to keep the patient in the study during
the 24-week placebo-controlled period.

Since this protocol was designed to reflect current clinical practice,
the following adjunctive treatments and dose adjustments were allowed:

-   Maximum of three intra-articular steroid injections were permitted
    during the first 3 months of the study (injected joint(s) were not
    assessed during joint examinations for 28 days following each
    injection).

-   Dose of background DMARD, steroid, or NSAID therapies could be
    adjusted once during the study; further dose adjustments were
    instituted only after consultation with the medical monitor.

**Secondary efficacy assessment - ACR20 response**

The efficacy analysis was performed on the "full analysis set" of
patients defined by the intent-to-treat principle. The full analysis set
was defined as all patients who were randomized and received at least
one injection of study drug and had at least one post-dose efficacy
assessment. The ACR20 response at Week 24 (change from baseline) (using
CRP as the acute phase reactant) was defined as the efficacy variable.
All patients with missing visits or who withdrew from the study
prematurely were counted as non-responders at the missing visits or from
the time point of premature discontinuation onwards.

ACR20 response rates of the adalimumab and placebo-treated groups were
compared using Pearson's *χ*^2^ test with a two-sided level of
significance of α=0.05. All other efficacy variables were summarized
descriptively (statistical characteristics, frequencies, percentages,
confidence intervals) and analyzed by exploratory two-sided statistical
tests. For categorical data, Pearson's χ^2^ test was used. For
continuous data, an analysis of covariance (ANCOVA) model was used that
included the treatment group as a factor and the respective baseline
value as a covariate. In case of baseline imbalances between the
treatment groups, further covariates could be added to the model.

A total of 400 patients were planned to be equally allocated to the two
treatment groups, adalimumab 40 mg every other week and placebo. This
sample size was chosen in order to increase the total number of patients
exposed to adalimumab to approximately 300, thus allowing the study to
be powered to show one adverse event with an incidence of 1% with at
least 95% probability and with an incidence of 0.4% with at least 70%
probability. Analysis of this enlarged safety database was intended for
evaluation of any differences in AEs between patients treated with
adalimumab *versus* standard rheumatologic care.

**B. Study Conduct**

Planned enrollment for this study was increased to 600 patients. Over
700 patients enrolled, 318 patients were randomized to each of the two
treatment arms (adalimumab and placebo), and 91% of patients randomized
to each treatment arm completed the study (Table 37). Dropouts occurred
equally in both groups (9%). However, the number of dropouts due to lack
of efficacy and/or progression of disease was higher in the
placebo-treated group than in the adalimumab-treatment group. No
increased incidence of withdrawals due to AEs was observed in the
adalimumab-treatment group compared to the placebo-treated group.

A summary of patient disposition (all randomized patients) is presented
in Figure 12 and

Table 37. Due to the fact that one of the investigators (Dr. DeAbate;
Site #7) was undergoing proceedings to be debarred, patients enrolled at
his site (6 patients) were removed from the efficacy analysis. All
randomized patients are included in the demographic and safety analyses.

> ![](media/image20.png){width="4.802083333333333in"
> height="5.416666666666667in"}
>
> Figure 12 : StudyDE031 : Patient Disposition

Table 37 : Study DE031 : Patient Disposition (Number \[%\] of Patients)
by Randomized Treatment Group (all randomized patients)

+------------------------------+------------+------------+------------+
|                              | *          |            |            |
|                              | *Treatment |            |            |
|                              | group**    |            |            |
+------------------------------+------------+------------+------------+
|                              | **Ad       | *          | **Total**  |
|                              | alimumab** | *Placebo** |            |
+------------------------------+------------+------------+------------+
| **Result**                   | *          | *          | *          |
|                              | *(N=318)** | *(N=318)** | *(N=636)** |
+------------------------------+------------+------------+------------+
| **Completed study**          | 290 (91)   | 288 (91)   | 578 (91)   |
+------------------------------+------------+------------+------------+
| **Early discontinuation**    | 28 (9)     | 30 (9)     | 58 (9)     |
+------------------------------+------------+------------+------------+
| **Early withdrawals due      |            |            |            |
| to:**                        |            |            |            |
+------------------------------+------------+------------+------------+
| **Adverse event**            | 9 (3)      | 8 (3)      | 17 (3)     |
+------------------------------+------------+------------+------------+
| **Lost to follow-up**        | 2 (1)      | 0 (0)      | 2 (0)      |
+------------------------------+------------+------------+------------+
| **Protocol deviations**      | 5 (2)      | 3 (1)      | 8 (1)      |
+------------------------------+------------+------------+------------+
| **Death**                    | 1 (0)      | 0 (0)      | 1 (0)      |
+------------------------------+------------+------------+------------+
| **Lack of efficacy and/or**  | **5 (2)**  | **14 (4)** | **19 (3)** |
|                              |            |            |            |
| **progression of disease**   |            |            |            |
+------------------------------+------------+------------+------------+
| **Administrative reasons**   | 6 (2)      | 5 (2)      | 11 (2)     |
+------------------------------+------------+------------+------------+

Table 38 : Study DE031 : Demographic characteristics at baseline by
randomized treatment group (all randomized patients)

+------------------------------+-------------------+-------------------+
|                              | **Adalimumab**    | **Placebo**       |
+------------------------------+-------------------+-------------------+
| # Demographic characteristic | **(N=318)**       | **(N=318)**       |
+------------------------------+-------------------+-------------------+
| **Mean Age (years)**         | 55                | 56                |
+------------------------------+-------------------+-------------------+
| **Female (%)**               | 80                | 79                |
+------------------------------+-------------------+-------------------+
| **Ethnicity**                |                   |                   |
+------------------------------+-------------------+-------------------+
| **Caucasian (%)**            | 89                | 86                |
+------------------------------+-------------------+-------------------+
| **Black (%)**                | 4                 | 6                 |
+------------------------------+-------------------+-------------------+
| **Hispanic (%)**             | 5                 | 6                 |
+------------------------------+-------------------+-------------------+
| **Mean Weight (kg)**         | 78                | 76                |
+------------------------------+-------------------+-------------------+
| **Mean RA duration (years)** | 9                 | 12                |
+------------------------------+-------------------+-------------------+
| **Rheumatoid Factor positive | 63                | 62                |
| (%)**                        |                   |                   |
+------------------------------+-------------------+-------------------+
| **RA-relevant previous       | 56                | 59                |
| disease**                    |                   |                   |
|                              |                   |                   |
| **(at least one) (%)**       |                   |                   |
+------------------------------+-------------------+-------------------+
| **Tender joint count         | 25                | 25                |
| (median)**                   |                   |                   |
+------------------------------+-------------------+-------------------+
| **Swollen joint count        | 18                | 19                |
| (median)**                   |                   |                   |
+------------------------------+-------------------+-------------------+
| Patient global assessment of | 53                | 52                |
| disease activity (mm on VAS) |                   |                   |
+------------------------------+-------------------+-------------------+
| **Patient assessment of      | 57                | 58                |
| pain**                       |                   |                   |
|                              |                   |                   |
| **(mm on VAS)**              |                   |                   |
+------------------------------+-------------------+-------------------+
| **Disability index (HAQ)**   | 1.38              | 1.38              |
+------------------------------+-------------------+-------------------+
| **CRP (mg/dL) (mean)**       | 1.5               | 1.5               |
+------------------------------+-------------------+-------------------+
| **FACIT Fatigue scale        | 30                | 30                |
| (median)**                   |                   |                   |
+------------------------------+-------------------+-------------------+
| **DMARD therapy**            |                   |                   |
+------------------------------+-------------------+-------------------+
| #                            | 56                | 56                |
| DMARD discontinued prior (%) |                   |                   |
+------------------------------+-------------------+-------------------+
| **Concomitant RA-specific    | 82                | 85                |
| DMARD therapy (%)**          |                   |                   |
+------------------------------+-------------------+-------------------+
| **Concomitant RA-specific    | 99                | 96                |
| non-DMARD therapy (%)**      |                   |                   |
+------------------------------+-------------------+-------------------+
| **Increase in DMARD dose     | 2                 | 4                 |
| (%)**                        |                   |                   |
+------------------------------+-------------------+-------------------+
| **Initiation of DMARD (%)**  | 1                 | 3                 |
+------------------------------+-------------------+-------------------+
| **Increase in steroid dose   | 4                 | 6                 |
| (%)**                        |                   |                   |
+------------------------------+-------------------+-------------------+
| **Tuberculin PPD at          |                   |                   |
| baseline**                   |                   |                   |
|                              |                   |                   |
| **(N/%)**                    |                   |                   |
+------------------------------+-------------------+-------------------+
| **PPD Positive**             | 7/2               | 4/1               |
+------------------------------+-------------------+-------------------+
| **PPD Positive-on            | 4/1               | 3/1               |
| prophylaxis**                |                   |                   |
+------------------------------+-------------------+-------------------+
| **PPD not stated-on          | 1/0               | 1/0               |
| prophylaxis**                |                   |                   |
+------------------------------+-------------------+-------------------+

A.  **Safety Analysis**

Comparable percentages of patients in the adalimumab and placebo
treatment groups reported one or more treatment-emergent AEs during the
study. The percentage of patients with AEs considered to be at least
possibly related to study drug according to the investigator's
assessment was higher in the adalimumab group than in the placebo group.
Injection site reaction was significantly greater in patients receiving
adalimumab than in patients receiving placebo. Neither the incidence of
SAEs nor severe or life-threatening AEs was higher in the
adalimumab-treated group. One death due to an AE was reported during the
study. Patient #15106, treated with adalimumab, died following a SAE of
herpes zoster, complicated by streptococcal superinfection (necrotizing
fasciitis). No significant differences in the incidences of severe or
life-threatening AEs, SAEs, or deaths were observed between the two
treatment groups (Table 39). Summarization of all safety issues will be
provide in the Integrated Safety Analysis.

Table 39 : Study DE031 : Overview of Patients with Treatment-Emergent
AEs (safety set)

+-----------------------+-------+--------+-------+--------+-----------+
|                       | **Ad  |        | *     |        | **Ada     |
|                       | alimu |        | *Plac |        | limumab** |
|                       | mab** |        | ebo** |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
|                       | **(N  |        | **(N  |        | ***vs.*** |
|                       | =     |        | =     |        |           |
|                       | 3     |        | 3     |        |           |
|                       | 18)** |        | 18)** |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
|                       | **(   |        | **(   |        | **        |
|                       | 141.2 |        | 139.9 |        | Placebo** |
|                       | pt-y  |        | pt-y  |        |           |
|                       | rs)** |        | rs)** |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| **Patients with       | **N   | *      | **N   | *      | **p\<     |
| any^a^**              | (%)** | *N/100 | (%)** | *N/100 | 0.05^c^** |
|                       |       | pt-yr  |       | pt-yr  |           |
|                       |       | s^b^** |       | s^b^** |           |
+-----------------------+-------+--------+-------+--------+-----------+
| AE                    | 275   | 194.8  | 263   | 188.0  | \-        |
|                       | (87)  |        | (83)  |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| AE leading to death   | 1 (0) | 0.7    | 0 (0) | 0.0    | \-        |
+-----------------------+-------+--------+-------+--------+-----------+
| SAE                   | 17    | 12.0   | 22    | 15.7   | \-        |
|                       | (5)   |        | (7)   |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| AE resulting in       | 9 (3) | 6.4    | 7 (2) | 5.0    | \-        |
| withdrawal            |       |        |       |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| AE resulting in dose  | 38    | 26.9   | 27    | 19.3   | \-        |
| interruption          | (12)  |        | (9)   |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| Severe or             | 38    | 26.9   | 49    | 35.0   | \-        |
| life-threatening AE   | (12)  |        | (15)  |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| At least possibly     | 147   | 104.1  | 111   | 79.3   | Yes       |
| drug-related AE       | (46)  |        | (35)  |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| Infection             | 166   | 117.6  | 157   | 112.2  | \-        |
|                       | (52)  |        | (49)  |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| Serious infection     | 4 (1) | 2.8    | 6 (2) | 4.3    | \-        |
+-----------------------+-------+--------+-------+--------+-----------+
| Malignancy            | 4 (1) | 2.8    | 0 (0) | 0.0    | Yes       |
+-----------------------+-------+--------+-------+--------+-----------+
| Immunologic reaction  | 1 (0) | 0.7    | 1 (0) | 0.7    | \-        |
+-----------------------+-------+--------+-------+--------+-----------+
| AE except injection   | 270   | 191.2  | 258   | 184.4  | \-        |
| site reaction         | (85)  |        | (81)  |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| At least possibly     | 117   | 82.9   | 89    | 63.6   | Yes       |
| drug-related AE       | (37)  |        | (28)  |        |           |
| except injection site |       |        |       |        |           |
| reaction              |       |        |       |        |           |
+-----------------------+-------+--------+-------+--------+-----------+
| ^a^ More than one AE  |       |        |       |        |           |
| per patient possible. |       |        |       |        |           |
|                       |       |        |       |        |           |
| ^b^ Number of         |       |        |       |        |           |
| patients with AEs per |       |        |       |        |           |
| 100 patient-years.    |       |        |       |        |           |
|                       |       |        |       |        |           |
| ^c^ Pearson's ^2^    |       |        |       |        |           |
| test.                 |       |        |       |        |           |
+-----------------------+-------+--------+-------+--------+-----------+

The numbers of patients reporting serious infections, malignancies, or
immunologic reactions during this study were very small. The incidence
of infections was similar for patients in the adalimumab and placebo
treatment groups. A higher proportion of serious infections were
reported in patients in the placebo-treated group (6 cases, 2%) compared
to the adalimumab-treated group (4 cases, 1%). A higher proportion of
patients in the adalimumab-treated group experienced malignancies (4
cases, 1%) compared to the placebo-treated patients (0 cases). The
malignancies observed in the adalimumab-treated patients were 3 cases of
basal cell carcinoma of the skin and one case of T-cell lymphoma.
Patient 11601 was noted to have enlarged lymph nodes after three doses
of study drug, was subsequently biopsied, and diagnosed with a T-cell
lymphoma. The nominal p-value for the incidence of malignancies was
\<0.05. However, this does not take into account the multiple
comparisons.

The mean duration and total number of injections of study drug were
comparable in patients who received adalimumab or placebo. The mean
total dose of adalimumab administered during the study was 481.4 mg.

A total of 9 (3%) of 318 adalimumab-treated patients and 7 (2%) of 318
placebo-treated patients withdrew from the study due to one or more
treatment-emergent AEs. A summary of all patients who experienced AEs
resulting in withdrawal is provided in Table 40. There were two cases of
rashes and two cases of infections (infected foot and herpes zoster)
among the adalimumab-treated patients leading to discontinuation from
the study.

Table 40 : Study DE031 Patients Withdrawn Due to Treatment-Emergent AEs
(safety set)

![](media/image21.png){width="5.791666666666667in" height="3.875in"}

Comparison of the AEs subsetted by concomitant DMARD subgroups is
summarized in

Table 41. A higher rate of certain categories of associated AEs with
certain concomitant DMARDs was seen. AEs resulted in a higher incidence
of dose interruption when leflunomide was combined with adalimumab (8
cases, 19%) compared to placebo (1 case, 2%). In addition, AEs at least
possibly adalimumab-related were more frequent when adalimumab was given
concomitantly with MTX, leflunomide, and other DMARDs, but not with
antimalarials and sulfasalazine. A higher rate of SAEs was seen among
placebo-treated patients than adalimumab-treated patients when given
concomitantly with MTX and antimalarials.

Comparison of the number (percentage) of patients with the most
frequently reported treatment-related AEs subsetted by number of
concomitant DMARDs, shows a higher incidence of AEs that were considered
drug-related when adalimumab is given alone or with one additional DMARD
compared to placebo. There was no clear pattern of an increase in AEs
overall among patients receiving adalimumab along with two or three
additional DMARDs (Table 42).

Comparison of the number (percentage) of patients with the most
frequently reported treatment-related AEs by concomitant DMARD therapy
does not demonstrate a higher frequency of adalimumab-related AEs (Table
43). Comparison of the number (percentage) of patients with the most
frequently reported treatment-related AEs corrected for frequency per
100 patient years reveals that rash, injection site reaction, and back
pain were seen more frequently among adalimumab-treated patients \\than
placebo-treated patients with a nominal p value of \< 0.05.

Table 41 : Study DE031 : Overview of Treatment-Emergent AEs by
Concomitant DMARD Therapy^a^ (safety set)

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 9%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 9%" />
<col style="width: 5%" />
<col style="width: 9%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"><strong>Methotrexate</strong></td>
<td colspan="2"><strong>Antimalarials</strong></td>
<td colspan="2"><strong>Leflunomide</strong></td>
<td colspan="2"><strong>Sulfasalazine</strong></td>
<td colspan="2"><strong>Other DMARDs</strong></td>
</tr>
<tr class="even">
<td></td>
<td><h3 id="adalimumab-6">Adalimumab</h3></td>
<td><h3 id="placebo-4">Placebo</h3></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
</tr>
<tr class="odd">
<td></td>
<td>(N=178)</td>
<td>(N=199)</td>
<td>(N=75)</td>
<td>(N=82)</td>
<td>(N=42)</td>
<td>(N=46)</td>
<td>(N=29)</td>
<td>(N=33)</td>
<td>(N=25)</td>
<td>(N=25)</td>
</tr>
<tr class="even">
<td><strong>Patients with any<sup>a</sup></strong></td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
<td>N (%)</td>
</tr>
<tr class="odd">
<td><strong>Adverse Event</strong></td>
<td>153 (86)</td>
<td>161 (81)</td>
<td>63 (84)</td>
<td>74 (90)</td>
<td>39 (93)</td>
<td>39 (85)</td>
<td>23 (80)</td>
<td>28 (85)</td>
<td>23 (92)</td>
<td>19 (76)</td>
</tr>
<tr class="even">
<td><strong>AE leading to death</strong></td>
<td>1 (1)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
</tr>
<tr class="odd">
<td><strong>SAE</strong></td>
<td>8 (5)</td>
<td>17 (9)</td>
<td>4 (5)</td>
<td>7 (9)</td>
<td>3 (7)</td>
<td>2 (4)</td>
<td>2 (7)</td>
<td>1 (3)</td>
<td>0 (0)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td><strong>AE resulting in withdrawal</strong></td>
<td>5 (3)</td>
<td>4 (2)</td>
<td>0 (0)</td>
<td>2 (2)</td>
<td>2 (5)</td>
<td>1 (2)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
</tr>
<tr class="odd">
<td><strong>AE resulting in dose interruption</strong></td>
<td>16 (9)</td>
<td>13 (7)</td>
<td>7 (9)</td>
<td>6 (7)</td>
<td>8 (19)</td>
<td>1 (2)</td>
<td>2 (7)</td>
<td>4 (12)</td>
<td>1 (4)</td>
<td>3 (12)</td>
</tr>
<tr class="even">
<td><strong>Severe or life-threatening AE</strong></td>
<td>19 (11)</td>
<td>28 (14)</td>
<td>7 (9)</td>
<td>13 (16)</td>
<td>8 (19)</td>
<td>8 (17)</td>
<td>5 (17)</td>
<td>5 (15)</td>
<td>1 (4)</td>
<td>2 (8)</td>
</tr>
<tr class="odd">
<td><strong>At least possibly drug-related AE</strong></td>
<td>78 (44)</td>
<td>67 (34)</td>
<td>37 (49)</td>
<td>40 (49)</td>
<td>23 (55)</td>
<td>18 (39)</td>
<td>14 (48)</td>
<td>14 (42)</td>
<td>14 (56)</td>
<td>9 (36)</td>
</tr>
<tr class="even">
<td><strong>Infection</strong></td>
<td>100 (56)</td>
<td>96 (48)</td>
<td>34 (45)</td>
<td>48 (59)</td>
<td>24 (57)</td>
<td>21 (46)</td>
<td>13 (45)</td>
<td>15 (46)</td>
<td>14 (56)</td>
<td>15 (60)</td>
</tr>
<tr class="odd">
<td><h2 id="serious-infection">Serious infection</h2></td>
<td>4 (2)</td>
<td>4 (2)</td>
<td>1 (1)</td>
<td>3 (4)</td>
<td>0 (0)</td>
<td>2 (4)</td>
<td>1 (3)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td><strong>Malignancy</strong></td>
<td>2 (1)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
</tr>
<tr class="odd">
<td><strong>Immunologic reaction</strong></td>
<td>0 (0)</td>
<td>1 (1)</td>
<td>0 (0)</td>
<td>1 (1)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>1 (3)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td colspan="11"><sup>a</sup> .More than one AE per patient
possible.</td>
</tr>
</tbody>
</table>

Table 42 : Study DE031 : Overview of Treatment-Emergent AEs by Number of
Concomitant DMARD Therapies (safety set)

  ------------------ ---------------- ------------- ------ ---------------- ------------- ---------------- ------------- ---------------- -------------
  **Number of        **0**                                 **1**                          **2**                          **3**            
  concomitant                                                                                                                             
  DMARDs**                                                                                                                                

                     **Adalimumab**   **Placebo**          **Adalimumab**   **Placebo**   **Adalimumab**   **Placebo**   **Adalimumab**   **Placebo**

                     **(N=57)**       **(N=48)**           **(N=184)**      **(N=172)**   **(N=66)**       **(N=84)**    **(N=11)**       **(N=14)**

  **Patients with    **N (%)**        **N (%)**            **N (%)**        **N (%)**     **N (%)**        **N (%)**     **N (%)**        **N (%)**
  any^a^**                                                                                                                                

  **AE**             46 (81)          36 (75)              166 (90)         145 (84)      54 (82)          72 (86)       9 (82)           10 (71)

  **AE leading to    0 (0)            0 (0)                1 (1)            0 (0)         0 (0)            0 (0)         0 (0)            0 (0)
  death**                                                                                                                                 

  **SAE**            3 (5)            2 (4)                12 (7)           13 (8)        1 (2)            7 (8)         1 (9)            0 (0)

  **AE resulting in  2 (4)            1 (2)                7 (4)            5 (3)         0 (0)            1 (1)         0 (0)            0 (0)
  withdrawal**                                                                                                                            

  **AE resulting in  10 (18)          4 (8)                22 (12)          19 (11)       6 (9)            4 (5)         0 (0)            0 (0)
  dose                                                                                                                                    
  interruption**                                                                                                                          

  **Severe or        7 (12)           7 (15)               23 (13)          30 (17)       7 (11)           10 (12)       1 (9)            2 (14)
  life-threatening                                                                                                                        
  AE**                                                                                                                                    

  **At least         **22 (39)**      **11 (23)**          **90 (49)**      **60 (35)**   **29 (44)**      **33 (39)**   **6 (55)**       **7 (50)**
  possibly                                                                                                                                
  drug-related AE**                                                                                                                       

  **Infection**      28 (49)          17 (35)       99                      93 (54)       31 (47)          41 (49)       8 (73)           6 (43)
                                                    (54)                                                                                  

  **Serious          0 (0)            0 (0)                3 (2)            3 (2)         0 (0)            3 (4)         1 (9)            0 (0)
  infection**                                                                                                                             

  **Malignancy**     2 (4)            0 (0)                2 (1)            0 (0)         0 (0)            0 (0)         0 (0)            0 (0)

  **Immunologic      0 (0)            0 (0)                1 (1)            0 (0)         0 (0)            1 (1)         0 (0)            0 (0)
  reaction**                                                                                                                              

  ^a^ More than one                                                                                                                       
  AE per patient                                                                                                                          
  possible.                                                                                                                               
  ------------------ ---------------- ------------- ------ ---------------- ------------- ---------------- ------------- ---------------- -------------

Table 43: Study DE031: Number (%) of Patients with The Most Frequently
Reported Treatment-Emergent AEs by Concomitant DMARD Therapy (safety
set)

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 10%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>AEs<sup>c</sup></strong></td>
<td colspan="2"><strong>Methotrexate</strong></td>
<td colspan="2"><strong>Antimalarials</strong></td>
<td colspan="2"><strong>Leflunomide</strong></td>
<td colspan="2"><strong>Sulfasalazine</strong></td>
<td colspan="2"><strong>Other</strong></td>
</tr>
<tr class="even">
<td></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
<td><strong>Adalimumab</strong></td>
<td><strong>Placebo</strong></td>
</tr>
<tr class="odd">
<td></td>
<td><strong>(N=178)</strong></td>
<td><strong>(N=199)</strong></td>
<td><strong>(N=75)</strong></td>
<td><strong>(N=82)</strong></td>
<td><strong>(N=42)</strong></td>
<td><strong>(N=46)</strong></td>
<td><strong>(N=29)</strong></td>
<td><strong>(N=33)</strong></td>
<td><strong>(N=25)</strong></td>
<td><strong>(N=25)</strong></td>
</tr>
<tr class="even">
<td></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
<td><strong>N (%)</strong></td>
</tr>
<tr class="odd">
<td><strong>Upper respiratory infection</strong></td>
<td>32 (18)</td>
<td>28 (14)</td>
<td>16 (21)</td>
<td>18 (22)</td>
<td>7 (17)</td>
<td>8 (17)</td>
<td>6 (21)</td>
<td>5 (15)</td>
<td>9 (36)</td>
<td>5 (20)</td>
</tr>
<tr class="even">
<td><strong>Injection site pain</strong></td>
<td>20 (11)</td>
<td>22 (11)</td>
<td>10 (13)</td>
<td>12 (15)</td>
<td>6 (14)</td>
<td>7 (15)</td>
<td>2 (7)</td>
<td>2 (6)</td>
<td>3 (12)</td>
<td>1 (4)</td>
</tr>
<tr class="odd">
<td><strong>Rash</strong></td>
<td>16 (9)</td>
<td>8 (4)</td>
<td>3 (4)</td>
<td>4 (5)</td>
<td>5 (12)</td>
<td>3 (7)</td>
<td>3 (10)</td>
<td>2 (6)</td>
<td>2 (8)</td>
<td>3 (12)</td>
</tr>
<tr class="even">
<td><strong>Injection site reaction</strong></td>
<td>13 (7)</td>
<td>2 (1)</td>
<td>8 (11)</td>
<td>2 (24)</td>
<td>4 (10)</td>
<td>0 (0)</td>
<td>3 (10)</td>
<td>1 (3)</td>
<td>2 (8)</td>
<td>0 (0)</td>
</tr>
<tr class="odd">
<td><strong>Nausea</strong></td>
<td>16 (9)</td>
<td>11 (6)</td>
<td>10 (13)</td>
<td>4 (5)</td>
<td>6 (14)</td>
<td>3 (7)</td>
<td>3 (10)</td>
<td>2 (6)</td>
<td>1 (4)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td><strong>Urinary tract infection</strong></td>
<td>21 (12)</td>
<td>10 (5)</td>
<td>6 (8)</td>
<td>7 (9)</td>
<td>5 (12)</td>
<td>1 (2)</td>
<td>0 (0)</td>
<td>2 (6)</td>
<td>1 (4)</td>
<td>2 (8)</td>
</tr>
<tr class="odd">
<td><strong>Headache</strong></td>
<td>13 (7)</td>
<td>13 (7)</td>
<td>12 (16)</td>
<td>9 (11)</td>
<td>3 (7)</td>
<td>2 (4)</td>
<td>3 (10)</td>
<td>3 (9)</td>
<td>0 (0)</td>
<td>1 (4)</td>
</tr>
<tr class="even">
<td><strong>Sinusitis</strong></td>
<td>16 (9)</td>
<td>13 (7)</td>
<td>9 (12)</td>
<td>9 (11)</td>
<td>2( 5)</td>
<td>2 (4)</td>
<td>0 (0)</td>
<td>2 (6)</td>
<td>0 (0)</td>
<td>4 (16)</td>
</tr>
<tr class="odd">
<td><strong>Flu syndrome</strong></td>
<td>13 (7)</td>
<td>7 (4)</td>
<td>5 (7)</td>
<td>3 (4)</td>
<td>2 (5)</td>
<td>2 (4)</td>
<td>2 (7)</td>
<td>1 (3)</td>
<td>2 (8)</td>
<td>3 (12)</td>
</tr>
<tr class="even">
<td><strong>Accidental injury</strong></td>
<td>16 (9)</td>
<td>11 (6)</td>
<td>6 (8)</td>
<td>9 (11)</td>
<td>3 (7)</td>
<td>4 (9)</td>
<td>3 (10)</td>
<td>3 (9)</td>
<td>1 (4)</td>
<td>2 (8)</td>
</tr>
<tr class="odd">
<td><strong>Abdominal pain</strong></td>
<td>9 (5)</td>
<td>9 (5)</td>
<td>2 (3)</td>
<td>5 (6)</td>
<td>2 (5)</td>
<td>1 (2)</td>
<td>3 (10)</td>
<td>1 (3)</td>
<td>0 (0)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td><strong>Rhinitis</strong></td>
<td>17 (10)</td>
<td>24 (12)</td>
<td>5 (7)</td>
<td>9 (11)</td>
<td>2 (5)</td>
<td>6 (13)</td>
<td>3 (10)</td>
<td>3 (9)</td>
<td>2 (8)</td>
<td>1 (4)</td>
</tr>
<tr class="odd">
<td><strong>Diarrhea</strong></td>
<td>14 (8)</td>
<td>12 (6)</td>
<td>6 (8)</td>
<td>7 (9)</td>
<td>3 (7)</td>
<td>7 (15)</td>
<td>1 (3)</td>
<td>2 (6)</td>
<td>1 (4)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td><strong>Clinical flare reaction</strong></td>
<td>8 (5)</td>
<td>10 (5)</td>
<td>3 (4)</td>
<td>5 (6)</td>
<td>3 (7)</td>
<td>3 (7)</td>
<td>4 (14)</td>
<td>2 (6)</td>
<td>1 (4)</td>
<td>2 (8)</td>
</tr>
<tr class="odd">
<td><strong>Back pain</strong></td>
<td>11 (6)</td>
<td>3 (2)</td>
<td>2 (3)</td>
<td>1 (1)</td>
<td>4 (10)</td>
<td>1 (2)</td>
<td>3 (10)</td>
<td>2 (6)</td>
<td>4 (16)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td><strong>Surgery</strong></td>
<td>8 (5)</td>
<td>6 (3)</td>
<td>5 (7)</td>
<td>3 (4)</td>
<td>3 (7)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>1 (3)</td>
<td>1 (4)</td>
<td>0 (0)</td>
</tr>
<tr class="odd">
<td colspan="11"><p><sup>a</sup> Occurring in 5% of patients in any
treatment group.</p>
<p><sup>b</sup> MTX = methotrexate; Antimal = antimalarials (eg, HCG,
chloroquine); Leflu = leflunomide; Sulfasal = sulfasalazine; Other =
other DMARDs.</p>
<p><sup>c</sup> More than one AE per patient possible.</p></td>
</tr>
</tbody>
</table>

Table 44 lists all the patients in Trial DE031 with SAEs. Eighteen
occurred among adalimumab-treated patients and 22 occurred among
placebo-treated patients. There was no clear pattern of SAEs among
adalimumab-treated patients.

Table 44 : Study DE031 : Patients with SAEs (safety set)

![](media/image22.png){width="5.854166666666667in"
height="7.552083333333333in"}

One adalimumab-treated patient (Patient #15106) died during the study
(Table 45). This patient developed herpes zoster 12 days after the first
injection of adalimumab, which then progressed into a streptococcal
group A superinfection at the site of the herpes lesions. This
progressed to necrotizing fasciitis and sepsis. The patient was admitted
to the hospital and underwent surgical debridement of the lesion. The
patient never recovered and died 16 days after the appearance of the
herpetic lesions. This adalimumab-treated patient was also taking
prednisone and methotrexate for control of RA.

Table 45 : Study DE031 Patient with fatal AE (safety set)

+--------+-----+---------+---------+------+------+------+------------+
| **Pat  | **  | **Trea  | **      | *    | **Du | **Se | **Relatio  |
| ient** | Age | tment** | Adverse | *Day | rati | veri | nship^a^** |
|        | Ge  |         | event** | on   | on** | ty** |            |
| **nu   | nde |         |         | dr   |      |      |            |
| mber** | r** |         | *       | ug** | **   |      |            |
|        |     |         | *(HARTS |      | (day |      |            |
|        |     |         | term)** | **at | s)** |      |            |
|        |     |         |         | ons  |      |      |            |
|        |     |         |         | et** |      |      |            |
+--------+-----+---------+---------+------+------+------+------------+
|        |     |         | **Skin  |      |      |      |            |
|        |     |         | dis     |      |      |      |            |
|        |     |         | order** |      |      |      |            |
+--------+-----+---------+---------+------+------+------+------------+
| **1    | **7 | **Adali | *       | **   | **   | *    | **         |
| 5106** | 0** | mumab** | *Herpes | 12** | 16** | *Gra | Possible** |
|        |     |         | zost    |      |      | de** |            |
|        | **  |         | er^b^** |      |      |      |            |
|        | Mal |         |         |      |      | **3, |            |
|        | e** |         |         |      |      | 4^   |            |
|        |     |         |         |      |      | b^** |            |
+--------+-----+---------+---------+------+------+------+------------+
| ^a^    |     |         |         |      |      |      |            |
| Relati |     |         |         |      |      |      |            |
| onship |     |         |         |      |      |      |            |
| to     |     |         |         |      |      |      |            |
| study  |     |         |         |      |      |      |            |
| drug   |     |         |         |      |      |      |            |
| as     |     |         |         |      |      |      |            |
| dete   |     |         |         |      |      |      |            |
| rmined |     |         |         |      |      |      |            |
| by the |     |         |         |      |      |      |            |
| i      |     |         |         |      |      |      |            |
| nvesti |     |         |         |      |      |      |            |
| gator. |     |         |         |      |      |      |            |
|        |     |         |         |      |      |      |            |
| ^b^    |     |         |         |      |      |      |            |
| Herpes |     |         |         |      |      |      |            |
| zoster |     |         |         |      |      |      |            |
| inf    |     |         |         |      |      |      |            |
| ection |     |         |         |      |      |      |            |
| began  |     |         |         |      |      |      |            |
| as a   |     |         |         |      |      |      |            |
| skin   |     |         |         |      |      |      |            |
| di     |     |         |         |      |      |      |            |
| sorder |     |         |         |      |      |      |            |
| of     |     |         |         |      |      |      |            |
| mo     |     |         |         |      |      |      |            |
| derate |     |         |         |      |      |      |            |
| se     |     |         |         |      |      |      |            |
| verity |     |         |         |      |      |      |            |
| and    |     |         |         |      |      |      |            |
| prog   |     |         |         |      |      |      |            |
| ressed |     |         |         |      |      |      |            |
| to     |     |         |         |      |      |      |            |
| s      |     |         |         |      |      |      |            |
| trepto |     |         |         |      |      |      |            |
| coccal |     |         |         |      |      |      |            |
| su     |     |         |         |      |      |      |            |
| perinf |     |         |         |      |      |      |            |
| ection |     |         |         |      |      |      |            |
| (necro |     |         |         |      |      |      |            |
| tizing |     |         |         |      |      |      |            |
| fasc   |     |         |         |      |      |      |            |
| iitis) |     |         |         |      |      |      |            |
| and    |     |         |         |      |      |      |            |
| s      |     |         |         |      |      |      |            |
| epsis. |     |         |         |      |      |      |            |
+--------+-----+---------+---------+------+------+------+------------+

Serious infectious AEs were reported in ten study patients, 4 (1.3% of
318) adalimumab-treated patients and 6 (1.9% of 318) placebo-treated
patients (Table 46). Among the adalimumab-treated patients, there were 2
cases of gastrointestinal disorder (appendicitis), 1 case of herpes
zoster, and 1 case of foot infection. Approximately 50% of both
adalimumab-treated and placebo-treated patients reported one or more
non-serious infectious AEs after study drug administration.

Table 46 : Study DE031 : Patients with serious infections (safety set)

![](media/image23.png){width="5.666666666666667in"
height="3.0520833333333335in"}

The six most frequently reported infectious AEs (upper respiratory
infection, rhinitis, sinusitis, urinary tract infection, flu syndrome,
and cough increased) are presented by concomitant DMARDs subgroups (with
and without methotrexate, antimalarials, leflunomide, sulfasalazine, or
other DMARDs) in Table 47 and summarized by the number of concomitant
DMARDs in Table 48. There was no clear pattern of an increase in any
particular type of infection beyond the fluctuations expected when large
numbers of comparisons are considered.

Although there were individual subgroups where the incidence of
particular infections was somewhat higher in adalimumab-treated patients
than in controls, there was no overall pattern of more frequent
infections associated with concomitant use of higher numbers of DMARDs
(Table 48).

Table 47: Study DE031 Frequent infectious adverse events by concomitant
DMARD therapy (safety set)

![](media/image24.png){width="8.5in" height="1.5520833333333333in"}

Table 48: Study DE031:Frequency of the most commonly reported infectious
adverse events by number of concomitant DMARD therapies (safety set)

![](media/image25.png){width="8.614583333333334in"
height="1.6979166666666667in"}

Similar numbers of adalimumab-treated patients and placebo-treated
patients withdrew from the study due to one or more treatment-emergent
AEs.

A higher percentage of adalimumab-treated patients converted from
negative to positive ANA than placebo-treated patients during this
trial. The percentage was notably higher at Week 24 than at Week 12
(Table 49 ).

Table 49 : Study DE031 : Patients who changed from positive to negative
or negative to positive ANA until Week 12 or Week 24 ^a^ (safety set)

![](media/image26.png){width="6.0in" height="1.5in"}

Likewise, a higher percentage of adalimumab-treated patients converted
from negative to positive anti-dsDNA than placebo-treated patients
during this trial. The percentage was much higher at Week 24 (Table 50
). One patient with rising ANA and anti-dsDNA titers was discontinued
from the study. No clinical manifestations of lupus-like syndrome were
observed among patients who became positive for autoantibodies.

Table 50: Study DE031 : Patients who changed from positive to negative
or negative to positive anti-dsDNA until Week 12 or Week 24 ^a^ (safety
set)

![](media/image27.png){width="6.010416666666667in"
height="1.5416666666666667in"}

> D. Efficacy Analysis

Clinical trial DE031 was designed to study the safety and efficacy of
adding adalimumab to DMARD regimens encountered in a typical clinical
practice. Adalimumab was given alone or in combination with other DMARDs
that patients were already receiving. The study assessed the efficacy of
adalimumab (40 mg) administered subcutaneously every other week for up
to 24 weeks in patients with RA whose disease was not adequately treated
with their current antirheumatic therapies. The efficacy assessment was
a comparison of the ACR20 response rates (using CRP as the acute phase
reactant) between adalimumab and placebo treatments. Adalimumab
demonstrated a greater degree of improvement (53%) than placebo (35%)
for the observed ACR20 response rate at Week 24 (Table 51).

Table 51 : Study DE031 :ACR20 response rate: number (%) of patients
responding over time by randomized treatment group (full analysis set)

![](media/image28.png){width="6.020833333333333in"
height="2.4895833333333335in"}

Since this study was designed to approximate usual clinical practice,
use of intra-articular injections and the ability to adjustment of DMARD
and corticosteroid doses were permitted. The frequency of increases in
DMARD and corticosteroid dosing was higher in the placebo group (Table
53) which would tend to increase the placebo response rate
disproportionately. This may have contributed to the relatively high 35%
ACR20 response rate at Week 24 (the highest ACR20 placebo response
observed in the clinical development program, when compared to the
placebo responses in trials DE009 \[13%\], DE011 \[19%\], and DE019
\[30%\]).

ACR20 response rates are displayed graphically over the 24 week time
course for adalimumab-treated patients and placebo-treated patients in
Figure 13. The onset of this response was rapid and sustained.

> ![](media/image29.png){width="5.729166666666667in"
> height="4.364583333333333in"}
>
> Figure 13 : Study DE031 :Time course of ACR20 responses by randomized
> treatment group

Adalimumab-treated patients taking concomitant methotrexate,
antimalarial treatments, or sulfasalazine demonstrated a higher ACR20
response rate than placebo patients taking similar DMARDs. However,
adalimumab patients taking concomitant leflunomide had a similar ACR20
response rate to placebo at Week 24 (33% and 37%, respectively) (Table
52). The patients receiving concomitant leflunomide were examined in
more detail to determine whether there was a reduced treatment effect of
adalimumab when added to leflunomide. First, earlier responses than Week
24 were examined. At Week 12, the ACR20 response rate for the adalimumab
patients taking concomitant leflunomide was 41%, and for placebo plus
leflunomide was 17%.

The lower response rate at Week 24 for adalimumab patients treated with
leflunomide may have been influenced by a number of factors:

> 1). The higher number of patient withdrawals in the adalimumab plus
> concomitant leflunomide group. Of the patients receiving concomitant
> leflunomide, 7 of 42 (17%) adalimumab-treated patients but only 3 of
> 46 (7%) placebo-treated patients were withdrawn from the study
> prematurely. There was no pattern of reasons for withdrawal in either
> group. Of note, three of the adalimumab-treated early withdrawal
> patients had demonstrated ACR20 responses prior to being withdrawn,
> compared to one of the placebo-treated early withdrawal patients.
>
> 2). Patients treated with placebo plus concomitant leflunomide had an
> increase in ACR20 response from Week 12 to 24 probably due to the
> greater use of rescue steroids in this group (30%) compared to
> adalimumab plus concomitant leflunomide (14%). Among patients taking
> concomitant leflunomide, 5 of 46 (11%) placebo patients but only 1 of
> 42 (2%) adalimumab-treated patients received rescue steroid treatment
> before reaching ACR20 criteria.

Furthermore, thirty-five of the placebo plus leflunomide patients in
this study rolled over into DE020, an open-label adalimumab 40 mg
biweekly study. Their ACR20 response rate increased from 23% at study
entry to 54% at Week 12.

Thus, the early withdrawals may have decreased the overall
adalimumab-treated patient response, and the higher ACR20 response rate
demonstrated by the placebo-treated patients in this study could be
attributed to the greater rescue initiation of DMARDs, increased dosages
of DMARDs and steroids, and intra-articular injections (Table 53). Data
detailing the frequency and medications utilized for intra-articular
injections were not provided.

Table 52: Study DE031 : Concomitant Medication at Week 24 for ACR20

  ------------------------- ---------------- ------------ ------------- ------------
                            **ACR 20**                                  

                            **Adalimumab**                **Placebo**   

  Concomitant medication    **Total N**      **%          **Total N**   **%
                                             Response**                 Response**

  Methotrexate              178              57           199           35

  Antimalarial              75               51           82            33

  Leflunomide               42               33           46            37

  Sulfasalazine             29               59           33            24

  Other DMARDs              25               52           25            44

  No DMARD                  54               50           45            33

  One DMARD                 184              55           172           38

  Two DMARDs                66               50           84            30

  Three or more DMARDs      11               46           14            36
  ------------------------- ---------------- ------------ ------------- ------------

Antimalarial (e.g., HCG, chloroquine)

Table 53: Study DE031 : Incidence of DMARD or Steroid Therapy Change

![](media/image30.png){width="5.999305555555556in"
height="1.4270833333333333in"}

> **E. Summary of Analyses for Study DE031**

This trial was designed to mimic typical clinical practice where
adalimumab would be given alone or in combination with other DMARDs. The
study assessed the efficacy of adalimumab administered 40 mg
subcutaneously every other week for up to 24 weeks to patients with RA
whose disease was not adequately treated with their current
antirheumatic therapies. The efficacy assessment, a comparison of the
ACR20 responses, demonstrated a greater degree of improvement in the
adalimumab-treated patients (53%) than placebo (35%) at 24 weeks.
Similar efficacy was seen for adalimumab regardless of the background
DMARD regimen

Comparable percentages of patients in the adalimumab and placebo
treatment groups reported one or more treatment-emergent AEs during the
study. However AEs considered to be at least possibly related to study
drug were more frequent in the adalimumab group than in the placebo
group. Injection site reaction was seen more frequently in patients
receiving adalimumab than in patients receiving placebo. The incidence
of infections was similar for patients in the adalimumab and placebo
treatment groups. The proportion of adalimumab-treated patients
experiencing serious infections was similar to placebo-treated controls.
However, there was one death in the adalimumab-treatment group in a
patient with herpes zoster complicated by streptococcal superinfection
(necrotizing fasciitis). No pattern of an increase in AEs or SAEs was
seen when adalimumab was combined with any specific DMARD or combination
of DMARDs.

A higher proportion of patients in the adalimumab-treated group
experienced malignancies compared to the placebo--treated patients. The
malignancies observed in the adalimumab-treated patients were three
cases of basal cell carcinoma and one case of T-cell lymphoma. The rate
of malignancies in patients receiving adalimumab will be considered
further in the Integrated Safety Analysis

A higher percentage of adalimumab-treated patients converted from
negative to positive ANA and positive anti-dsDNA than placebo-treated
patients during this trial. No clinical autoimmune disease was observed.
The evidence of auto antibodies and autoimmune disease will be discussed
further in the Integrated Safety Analysis.

VI\. Integrated Safety Analysis

A. Safety Database

Safety data from all US and non-US (Europe, Australia, and Canada)
sources that were available as of August 31, 2001 were integrated within
this integrated summary of safety information (hereafter referred to as
the 'ISS') to provide a comprehensive safety profile for adalimumab in
this patient population. Safety data related to deaths, malignancies,
serious adverse events, and serious infections were up-dated as of
August 31, 2002. A total of 20 clinical trials completed during the
adalimumab clinical development program are included in the integrated
safety database (Table 54).

Table 54: ISS : Studies contributing safety information to the
adalimumab integrated safety database

![](media/image31.png){width="6.4944444444444445in"
height="3.022222222222222in"}

![](media/image32.png){width="6.498611111111111in"
height="2.4805555555555556in"}

Source of data: sponsor's ISS Table 1

AUS: Australia ; EU: Europe ; NA : North America (including U.S. and
Canada) ; CAN : Canada

MTX = methotrexate ; pbo-ctrl = placebo-controlled

^a^ Includes a 9-month blinded continuation period that followed DE017

The overall body of adalimumab safety data presented in this section
evaluates safety concerns

related to:

-   The short- and long-term safety and tolerability of adalimumab.

-   Safety of adalimumab when used alone or in combination with
    methotrexate or other DMARDs.

-   Safety of adalimumab when administered subcutaneously at the
    recommended dose of 40 mg every other week, and at the higher dose
    of 40 mg weekly.

-   Adverse events (AEs) experienced by RA patients treated with
    adalimumab, frequency and severity.

-   Incidences and types of serious infections, malignancies, autoimmune
    disorders, and deaths associated with adalimumab treatment,
    particularly in patients exposed to higher than recommended doses.

-   Incidence and effects of elevated anti-nuclear antibodies (ANAs),
    anti-double stranded

> deoxyribonucleic acid (anti-dsDNA) titers, and human anti-human
> antibodies (HAHAs) observed in some RA patients treated with
> adalimumab.

-   Any apparent effect on the safety profile of adalimumab by the
    development of HAHAs

or by prolonged dose interruptions.

Overall, the mean age of the patients treated with adalimumab was 55
years. Most adalimumab-treated patients (77%) were female, and the
majority of adalimumab-treated patients (91%) were Caucasian. The mean
duration of RA was 131 months and 80% of subjects were RF positive at
baseline. Many of the patients were receiving DMARDs at baseline and
during the studies. Concomitant medications included MTX in 49% of all
patients and corticosteroids in 57%. With regard to co-morbid conditions
among patients, hypertension was reported in 27%, diabetes in 6%, COPD
in 4%, and CHF in 1% of patients**.**

A total of approximately 1600 patients received treatment with
adalimumab at the proposed dosage of 40 mg biweekly for ≥ 6 months and
approximately 800 patients received treatment at that dose for ≥ 12
months (Table 55). The supplemental safety update provided safety data
for approximately 2400 adalimumab-treated patients.

Table 55: ISS : Summary of the Duration of Exposure to Adalimumab by
Treatment Received in all RA Patients

+---------+-------+-------+-------+-------+-------+-------+-------+
|         | Adali |       |       |       |       |       |       |
|         | mumab |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
|         | 20 mg | 20 mg | **40  | 40 mg | All   | All   | All   |
|         |       |       | mg**  |       |       |       |       |
|         | Q2w   | wk sc |       | wk sc | sc    | iv    | adali |
|         | sc    |       | **Q2w |       | dos   | dos   | mumab |
|         |       | (N    | sc**  | (N    | es^b^ | es^c^ |       |
|         | (N    | =397) |       | =466) |       |       | (N=   |
|         | =175) |       | **    |       | (N=   | (N    | 2334) |
|         |       |       | (N=19 |       | 2263) | =197) |       |
|         |       |       | 03)** |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
|         |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **D     |       |       |       |       |       |       |       |
| uration |       |       |       |       |       |       |       |
| of**    |       |       |       |       |       |       |       |
|         |       |       |       |       |       |       |       |
| *       |       |       |       |       |       |       |       |
| *exposu |       |       |       |       |       |       |       |
| re^a^** |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
|         | N (%) | N (%) | **N   | N (%) | N (%) | N (%) | N (%) |
|         |       |       | (%)** |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **\<3   | 23    | 39    | **117 | 55    | 95    | 31    | 109   |
| month** | (13)  | (10)  | (6)** | (12)  | (4)   | (16)  | (5)   |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **3-\<6 | 41    | 49    | **193 | 78    | 139   | 17    | 152   |
| m       | (23)  | (12)  | (     | (17)  | (6)   | (9)   | (7)   |
| onths** |       |       | 10)** |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| *       | 111   | 108   | **798 | 151   | 593   | 14    | 576   |
| *6-\<12 | (63)  | (27)  | (     | (32)  | (26)  | (7)   | (25)  |
| m       |       |       | 42)** |       |       |       |       |
| onths** |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **      | 0 (0) | 200   | **669 | 88    | 945   | 46    | 908   |
| 12-\<18 |       | (50)  | (     | (19)  | (42)  | (23)  | (39)  |
| m       |       |       | 35)** |       |       |       |       |
| onths** |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **      | 0 (0) | 0 (0) | **122 | 48    | 214   | 9 (5) | 195   |
| 18-\<24 |       |       | (6)** | (10)  | (10)  |       | (8)   |
| m       |       |       |       |       |       |       |       |
| onths** |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **      | 0 (0) | 1 (0) | **4   | 46    | 195   | 32    | 241   |
| 24-\<36 |       |       | (0)** | (10)  | (9)   | (16)  | (10)  |
| m       |       |       |       |       |       |       |       |
| onths** |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **      | 0 (0) | 0 (0) | **0   | 0 (0) | 82    | 48    | 108   |
| 36-\<48 |       |       | (0)** |       | (4)   | (24)  | (5)   |
| m       |       |       |       |       |       |       |       |
| onths** |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| **48   | 0 (0) | 0 (0) | **0   | 0 (0) | 0 (0) | 0 (0) | 45    |
| m       |       |       | (0)** |       |       |       | (2)   |
| onths** |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+
| > wk =  |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  weekly |       |       |       |       |       |       |       |
| > Q2w = |       |       |       |       |       |       |       |
| > every |       |       |       |       |       |       |       |
| > other |       |       |       |       |       |       |       |
| > week  |       |       |       |       |       |       |       |
| > sc =  |       |       |       |       |       |       |       |
| > subcu |       |       |       |       |       |       |       |
| taneous |       |       |       |       |       |       |       |
| > iv =  |       |       |       |       |       |       |       |
| > intr  |       |       |       |       |       |       |       |
| avenous |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| > ^a^   |       |       |       |       |       |       |       |
| > The   |       |       |       |       |       |       |       |
| > d     |       |       |       |       |       |       |       |
| uration |       |       |       |       |       |       |       |
| > in    |       |       |       |       |       |       |       |
| tervals |       |       |       |       |       |       |       |
| > are   |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| defined |       |       |       |       |       |       |       |
| > as    |       |       |       |       |       |       |       |
| > f     |       |       |       |       |       |       |       |
| ollows: |       |       |       |       |       |       |       |
| > \<3   |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| > 1-90  |       |       |       |       |       |       |       |
| > days; |       |       |       |       |       |       |       |
| > 3-\<6 |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  91-163 |       |       |       |       |       |       |       |
| > days; |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  6-\<12 |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| 164-344 |       |       |       |       |       |       |       |
| > days; |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| 12-\<18 |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| 345-527 |       |       |       |       |       |       |       |
| > days; |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| 18-\<24 |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| 528-709 |       |       |       |       |       |       |       |
| > days; |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| 24-\<36 |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| > 7     |       |       |       |       |       |       |       |
| 10-1074 |       |       |       |       |       |       |       |
| > days; |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| 36-\<48 |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| > 10    |       |       |       |       |       |       |       |
| 75-1439 |       |       |       |       |       |       |       |
| > days; |       |       |       |       |       |       |       |
| > 48   |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  months |       |       |       |       |       |       |       |
| > =     |       |       |       |       |       |       |       |
| > 1440 |       |       |       |       |       |       |       |
| > days. |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| > ^b^   |       |       |       |       |       |       |       |
| > i     |       |       |       |       |       |       |       |
| ncludes |       |       |       |       |       |       |       |
| > 80    |       |       |       |       |       |       |       |
| > (1.0  |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
|  mg/kg) |       |       |       |       |       |       |       |
| > eow   |       |       |       |       |       |       |       |
| > or    |       |       |       |       |       |       |       |
| > wk.   |       |       |       |       |       |       |       |
| >       |       |       |       |       |       |       |       |
| > ^c^   |       |       |       |       |       |       |       |
| > 0.25, |       |       |       |       |       |       |       |
| > 0.50, |       |       |       |       |       |       |       |
| > 1.0,  |       |       |       |       |       |       |       |
| > 3.0,  |       |       |       |       |       |       |       |
| > 5.0,  |       |       |       |       |       |       |       |
| > 10.0  |       |       |       |       |       |       |       |
| > mg/kg |       |       |       |       |       |       |       |
| > eow   |       |       |       |       |       |       |       |
| > or    |       |       |       |       |       |       |       |
| > wk.   |       |       |       |       |       |       |       |
+---------+-------+-------+-------+-------+-------+-------+-------+

**B. Treatment-Emergent Adverse Events**

Table 56 presents an overview of adverse events observed during the
adequate and well-controlled trials. Because patients receiving
different regimens had widely varying duration of exposure, rates are
calculated as events per 100 patient-years to provide a common metric.
Four categories of events of special interest were observed to occur
among patients at a higher frequency per 100 patient-years in the
adalimumab-treatment groups compared to placebo: deaths, drug-related
AEs, deaths, malignancies, and infections (serious and non-serious).
These will be described in more detail.

Table 56 : ISS : Overview of number (number/100 patient years) of
patients with treatment-emergent AEs during the placebo-controlled
period, by randomized treatment -- adequate and well-controlled studies
(safety set)

<table style="width:100%;">
<colgroup>
<col style="width: 15%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="13"><h6 id="adalimumab-7">Adalimumab</h6></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2" rowspan="2"><p>20 mg Q2w sc</p>
<p>(N=175)</p></td>
<td colspan="2" rowspan="2"><p>20 mg wk sc</p>
<p>(N=324)</p></td>
<td colspan="2" rowspan="2"><p><strong>40 mg Q2w sc</strong></p>
<p><strong>(N=705)</strong></p></td>
<td colspan="2" rowspan="2"><p>40 mg wk sc</p>
<p>(N=103)</p></td>
<td colspan="2" rowspan="2"><p>80 mg Q2w sc</p>
<p>(N=73)</p></td>
<td colspan="2" rowspan="2"><p>All adalimumab</p>
<p>(N=1380)</p></td>
<td colspan="3" rowspan="2"><p><strong>Placebo</strong></p>
<p><strong>(N=690)</strong></p></td>
</tr>
<tr class="odd">
<td></td>
</tr>
<tr class="even">
<td rowspan="2"><p><strong>Patients with any <sup>a</sup></strong></p>
<p><strong>AE</strong></p></td>
<td colspan="2">N (N/100PY)</td>
<td colspan="2">N (N/100PY)</td>
<td colspan="2"><strong>N (N/100PY)</strong></td>
<td colspan="2">N (N/100PY)</td>
<td colspan="2">N (N/100PY)</td>
<td colspan="2">N (N/100PY)</td>
<td colspan="3"><strong>N (N/100PY)</strong></td>
</tr>
<tr class="odd">
<td>170</td>
<td>(238)</td>
<td>312</td>
<td>(132)</td>
<td><strong>638</strong></td>
<td><strong>(160)</strong></td>
<td>102</td>
<td>(211)</td>
<td>64</td>
<td>(205)</td>
<td>1286</td>
<td>(164)</td>
<td colspan="2"><strong>598</strong></td>
<td><strong>(165)</strong></td>
</tr>
<tr class="even">
<td><strong>Clinical AE</strong></td>
<td>165</td>
<td>(231)</td>
<td>298</td>
<td>(126)</td>
<td><strong>620</strong></td>
<td><strong>(156)</strong></td>
<td>97</td>
<td>(201)</td>
<td>64</td>
<td>(205)</td>
<td>1244</td>
<td>(158)</td>
<td colspan="2"><strong>573</strong></td>
<td><strong>(158)</strong></td>
</tr>
<tr class="odd">
<td><strong>Laboratory AE</strong></td>
<td>106</td>
<td>(148)</td>
<td>152</td>
<td>(64)</td>
<td><strong>216</strong></td>
<td><strong>(54)</strong></td>
<td>89</td>
<td>(184)</td>
<td>6</td>
<td>(19)</td>
<td>569</td>
<td>(72)</td>
<td colspan="2"><strong>178</strong></td>
<td><strong>(49)</strong></td>
</tr>
<tr class="even">
<td><strong>Fatal AE</strong></td>
<td>0</td>
<td>(0.0)</td>
<td>1</td>
<td>(0.4)</td>
<td><strong>5</strong></td>
<td><strong>(1.3)</strong></td>
<td>1</td>
<td>(2.1)</td>
<td>0</td>
<td>(0)</td>
<td><strong>7</strong></td>
<td><strong>(0.9)</strong></td>
<td colspan="2"><strong>1</strong></td>
<td><strong>(0.3)</strong></td>
</tr>
<tr class="odd">
<td><strong>SAE</strong></td>
<td>17</td>
<td>(24)</td>
<td>53</td>
<td>(23)</td>
<td><strong>61</strong></td>
<td><strong>(15)</strong></td>
<td>14</td>
<td>(29)</td>
<td>6</td>
<td>(19)</td>
<td>151</td>
<td>(19)</td>
<td colspan="2"><strong>60</strong></td>
<td><strong>(17)</strong></td>
</tr>
<tr class="even">
<td><strong>AE leading to withdrawal</strong></td>
<td>11</td>
<td>(15)</td>
<td>27</td>
<td>(11)</td>
<td><strong>45</strong></td>
<td><strong>(11)</strong></td>
<td>5</td>
<td>(10)</td>
<td>3</td>
<td>(10)</td>
<td>91</td>
<td>(12)</td>
<td colspan="2"><strong>29</strong></td>
<td><strong>(8)</strong></td>
</tr>
<tr class="odd">
<td><strong>AE leading to dose interruption</strong></td>
<td>16</td>
<td>(22)</td>
<td>74</td>
<td>(31)</td>
<td><strong>103</strong></td>
<td><strong>(26)</strong></td>
<td>17</td>
<td>(35)</td>
<td>14</td>
<td>(45)</td>
<td>224</td>
<td>(29)</td>
<td colspan="2"><strong>86</strong></td>
<td><strong>(24)</strong></td>
</tr>
<tr class="even">
<td><strong>AE leading to dose reduction</strong></td>
<td>0</td>
<td>(0.0)</td>
<td>1</td>
<td>(0)</td>
<td><strong>0</strong></td>
<td><strong>(0)</strong></td>
<td>0</td>
<td>(0)</td>
<td>0</td>
<td>(0)</td>
<td>1</td>
<td>(0)</td>
<td colspan="2"><strong>0</strong></td>
<td><strong>(0)</strong></td>
</tr>
<tr class="odd">
<td><strong>Severe or life-threatening/intractable AE</strong></td>
<td>45</td>
<td>(63)</td>
<td>83</td>
<td>(35)</td>
<td><strong>113</strong></td>
<td><strong>(28)</strong></td>
<td>22</td>
<td>(46)</td>
<td>7</td>
<td>(22)</td>
<td>270</td>
<td>(34)</td>
<td colspan="2"><strong>114</strong></td>
<td><strong>(32)</strong></td>
</tr>
<tr class="even">
<td><strong>At least possibly drug-related AE</strong></td>
<td>112</td>
<td>(156.7)</td>
<td>198</td>
<td>(84.0)</td>
<td><strong>376</strong></td>
<td><strong>(94)</strong></td>
<td>71</td>
<td>(146.9)</td>
<td>35</td>
<td>(112.0)</td>
<td>792</td>
<td>(100.8)</td>
<td colspan="2"><strong>280</strong></td>
<td><strong>(77)</strong></td>
</tr>
<tr class="odd">
<td><strong>Infection (serious and non-serious)</strong></td>
<td>93</td>
<td>(130.1)</td>
<td>196</td>
<td>(83.1)</td>
<td><strong>398</strong></td>
<td><strong>(100)</strong></td>
<td>51</td>
<td>(105.5)</td>
<td>45</td>
<td>(144.1)</td>
<td>783</td>
<td>(99.7)</td>
<td colspan="2"><strong>334</strong></td>
<td><strong>(92)</strong></td>
</tr>
<tr class="even">
<td><strong>Serious infection</strong></td>
<td>2</td>
<td>(2.8)</td>
<td>10</td>
<td>(4.2)</td>
<td><strong>18</strong></td>
<td><strong>(4.5)</strong></td>
<td>3</td>
<td>(6.2)</td>
<td>1</td>
<td>(3.2)</td>
<td>34</td>
<td>(4.3)</td>
<td colspan="2"><strong>7</strong></td>
<td><strong>(1.9)</strong></td>
</tr>
<tr class="odd">
<td><strong>Malignancy</strong></td>
<td>2</td>
<td>(2.8)</td>
<td>5</td>
<td>(2.1)</td>
<td><strong>10</strong></td>
<td><strong>(2.5)</strong></td>
<td>1</td>
<td>(2.1)</td>
<td>1</td>
<td>(3.2)</td>
<td>19</td>
<td>(2.4)</td>
<td colspan="2"><strong>2</strong></td>
<td><strong>(&lt;1)</strong></td>
</tr>
<tr class="even">
<td><strong>Immunologic reaction</strong></td>
<td>1</td>
<td>(1.4)</td>
<td>2</td>
<td>(0.8)</td>
<td><strong>6</strong></td>
<td><strong>(1.5)</strong></td>
<td>1</td>
<td>(2.1)</td>
<td>0</td>
<td>(0)</td>
<td>10</td>
<td>(1.3)</td>
<td colspan="2"><strong>4</strong></td>
<td><strong>(1.1)</strong></td>
</tr>
<tr class="odd">
<td colspan="16"><blockquote>
<p>wk = weekly Q2w = every other week sc = subcutaneous</p>
<p><sup>a</sup> More than one AE per patient possible.</p>
</blockquote></td>
</tr>
</tbody>
</table>

The most frequently observed adverse drug reactions were injection site
reactions, rhinitis, upper respiratory infection, abnormal laboratory
test, and rash.

The rate of adverse events was approximately one AE per year and one
serious event per 4 to 5 years among adalimumab-treated and
placebo-treated patients. Adalimumab-treated patients experienced a
higher incidence of laboratory AEs and serious infections (Table 57).

Table 57 : ISS :Overview of number (%) of patients with
treatment-emergent AEs in patients treated with adalimumab during
placebo-controlled and non-placebo-controlled periods, by treatment
received -- all studies in RA patients (safety set)

<table style="width:100%;">
<colgroup>
<col style="width: 22%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4"><p><strong>Adalimumab</strong></p>
<p><strong>40 mg Q2w sc</strong></p>
<p><strong>(N=1903)</strong></p></td>
<td colspan="4"><p><strong>All adalimumab doses sc and iv</strong></p>
<p><strong>(N=2334)</strong></p></td>
<td colspan="4"><h4
id="placebo-treated-patients-from-the-adequate-and">Placebo-Treated
Patients from the Adequate and</h4>
<h4 id="well-controlled-studies">Well-Controlled Studies</h4>
<p><strong>(N=690)</strong></p></td>
</tr>
<tr class="even">
<td><strong>Patients with any<sup>a</sup></strong></td>
<td colspan="2"><strong>N (%)</strong></td>
<td colspan="2"><p><strong>E (E/100</strong></p>
<p><strong>pt-yrs)</strong></p></td>
<td colspan="2"><strong>N (%)</strong></td>
<td colspan="2"><p><strong>E (E/100</strong></p>
<p><strong>pt-yrs)</strong></p></td>
<td colspan="2"><strong>N (%)</strong></td>
<td colspan="2"><p><strong>E (E/100</strong></p>
<p><strong>pt-yrs)</strong></p></td>
</tr>
<tr class="odd">
<td>AE</td>
<td>1765</td>
<td>(93)</td>
<td>12172</td>
<td><strong>(786)</strong></td>
<td>2221</td>
<td><blockquote>
<p>(95)</p>
</blockquote></td>
<td>30775</td>
<td><strong>(1042)</strong></td>
<td>589</td>
<td>(87)</td>
<td>3304</td>
<td><strong>(912)</strong></td>
</tr>
<tr class="even">
<td>Clinical AE</td>
<td><strong>1675</strong></td>
<td><strong>(88)</strong></td>
<td><strong>9003</strong></td>
<td><strong>(582)</strong></td>
<td><strong>2180</strong></td>
<td><blockquote>
<p><strong>(93)</strong></p>
</blockquote></td>
<td><strong>19699</strong></td>
<td><strong>(667)</strong></td>
<td><strong>573</strong></td>
<td><strong>(83)</strong></td>
<td><strong>2769</strong></td>
<td><strong>(764)</strong></td>
</tr>
<tr class="odd">
<td>Laboratory AE</td>
<td><strong>886</strong></td>
<td><strong>(47)</strong></td>
<td><strong>3169</strong></td>
<td><strong>(205)</strong></td>
<td><strong>1201</strong></td>
<td><blockquote>
<p><strong>(52)</strong></p>
</blockquote></td>
<td><strong>11076</strong></td>
<td><strong>(375)</strong></td>
<td><strong>178</strong></td>
<td><strong>(26)</strong></td>
<td><strong>535</strong></td>
<td><strong>(148)</strong></td>
</tr>
<tr class="even">
<td>Fatal AE<sup>b</sup></td>
<td>9</td>
<td>(1)</td>
<td>16</td>
<td><strong>(1)</strong></td>
<td>22</td>
<td><blockquote>
<p>(1)</p>
</blockquote></td>
<td>41</td>
<td><strong>(1)</strong></td>
<td>1</td>
<td>(0)</td>
<td>3</td>
<td><strong>(1)</strong></td>
</tr>
<tr class="odd">
<td>SAE</td>
<td>294</td>
<td>(15)</td>
<td>404</td>
<td><strong>(26)</strong></td>
<td>575</td>
<td><blockquote>
<p>(25)</p>
</blockquote></td>
<td>1022</td>
<td><strong>(35)</strong></td>
<td>60</td>
<td>(9)</td>
<td>75</td>
<td><strong>(21)</strong></td>
</tr>
<tr class="even">
<td>AE leading to withdrawal</td>
<td>114</td>
<td>(6)</td>
<td>162</td>
<td><strong>(11)</strong></td>
<td>252</td>
<td><blockquote>
<p>(11)</p>
</blockquote></td>
<td>353</td>
<td><strong>(12)</strong></td>
<td>29</td>
<td>(4)</td>
<td>39</td>
<td><strong>(11)</strong></td>
</tr>
<tr class="odd">
<td>AE leading to dose interruption</td>
<td>340</td>
<td>(18)</td>
<td>522</td>
<td><strong>(34)</strong></td>
<td>614</td>
<td><blockquote>
<p>(26)</p>
</blockquote></td>
<td>1106</td>
<td><strong>(37)</strong></td>
<td>86</td>
<td>(13)</td>
<td>124</td>
<td><strong>(34)</strong></td>
</tr>
<tr class="even">
<td>AE leading to dose reduction</td>
<td>2</td>
<td>(0)</td>
<td>2</td>
<td><strong>(0)</strong></td>
<td>23</td>
<td><blockquote>
<p>(1)</p>
</blockquote></td>
<td>43</td>
<td><strong>(2)</strong></td>
<td>0</td>
<td>(0)</td>
<td>0</td>
<td><strong>(0)</strong></td>
</tr>
<tr class="odd">
<td>Severe or life-threatening/intractable AE</td>
<td>372</td>
<td>(20)</td>
<td>610</td>
<td><strong>(39)</strong></td>
<td>734</td>
<td><blockquote>
<p>(31)</p>
</blockquote></td>
<td>1482</td>
<td><strong>(50)</strong></td>
<td>114</td>
<td>(17)</td>
<td>220</td>
<td><strong>(61)</strong></td>
</tr>
<tr class="even">
<td>At least possibly drug-related AE</td>
<td>984</td>
<td>(52)</td>
<td>3214</td>
<td><strong>(208)</strong></td>
<td>1550</td>
<td><blockquote>
<p>(66)</p>
</blockquote></td>
<td>8620</td>
<td><strong>(292)</strong></td>
<td>280</td>
<td>(41)</td>
<td>850</td>
<td><strong>(235)</strong></td>
</tr>
<tr class="odd">
<td>Infection (serious and non-serious)</td>
<td>1061</td>
<td>(56)</td>
<td>2209</td>
<td><strong>(143)</strong></td>
<td>1573</td>
<td><blockquote>
<p>(67)</p>
</blockquote></td>
<td>4507</td>
<td><strong>(153)</strong></td>
<td>334</td>
<td>(48)</td>
<td>591</td>
<td><strong>(163)</strong></td>
</tr>
<tr class="even">
<td>Serious infection</td>
<td>56</td>
<td>(3)</td>
<td>61</td>
<td><strong>(4)</strong></td>
<td>129</td>
<td><blockquote>
<p>(6)</p>
</blockquote></td>
<td>146</td>
<td><strong>(5)</strong></td>
<td>7</td>
<td>(1)</td>
<td>7</td>
<td><strong>(2)</strong></td>
</tr>
<tr class="odd">
<td>Malignancy</td>
<td>29</td>
<td>(2)</td>
<td>30</td>
<td><strong>(2)</strong></td>
<td>52</td>
<td><blockquote>
<p>(2)</p>
</blockquote></td>
<td>53</td>
<td><strong>(2)</strong></td>
<td>2</td>
<td>(0)</td>
<td>2</td>
<td><strong>(1)</strong></td>
</tr>
<tr class="even">
<td>Immunologic reaction</td>
<td>16</td>
<td>(1)</td>
<td>19</td>
<td><strong>(1)</strong></td>
<td>38</td>
<td><blockquote>
<p>(2)</p>
</blockquote></td>
<td>49</td>
<td><strong>(2)</strong></td>
<td>4</td>
<td>(1)</td>
<td>4</td>
<td><strong>(1)</strong></td>
</tr>
<tr class="odd">
<td colspan="13"><p>Q2w = every other week sc = subcutaneous iv =
intravenous</p>
<p><sup>a</sup> More than one AE per patient possible.</p>
<p><sup>b</sup> Can include more than one AE ongoing at time of
death.</p></td>
</tr>
</tbody>
</table>

Increasing age among adalimumab-treated patients is associated with an
increased frequency of occurrence of malignancies, SAEs, and AEs
resulting in dose interruption (Table 58). These percentages increased
as age increased over 65 and even higher over age 75 in both those
patients treated with adalimumab and those receiving placebo. The
percentage of patients with fatal AEs, which only occurred in the
adalimumab--treated group, also increased in frequency with advancing
age.

Table 58 : ISS : Overview of number (%) of patients with
treatment-emergent AEs, by age - adequate and well controlled studies
(safety set)

<table style="width:100%;">
<colgroup>
<col style="width: 30%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="6"><p><strong>Adalimumab</strong></p>
<p><strong>40 mg Q2w sc</strong></p></td>
<td colspan="6"><strong>Placebo</strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2" rowspan="2"><p><strong>&lt;65</strong></p>
<p><strong>(N=526)</strong></p></td>
<td colspan="2" rowspan="2"><p><strong>65</strong></p>
<p><strong>(N=179)</strong></p></td>
<td colspan="2" rowspan="2"><p><strong>75</strong></p>
<p><strong>(N=42)</strong></p></td>
<td colspan="2" rowspan="2"><p><strong>&lt;65</strong></p>
<p><strong>(N=520)</strong></p></td>
<td colspan="2" rowspan="2"><p><strong>65</strong></p>
<p><strong>(N=170)</strong></p></td>
<td colspan="2" rowspan="2"><p><strong>75</strong></p>
<p><strong>(N=34)</strong></p></td>
</tr>
<tr class="odd">
<td></td>
</tr>
<tr class="even">
<td rowspan="2">Patients with any<sup>a</sup> AE</td>
<td>N</td>
<td>%</td>
<td>N</td>
<td>%</td>
<td>N</td>
<td><blockquote>
<p>%</p>
</blockquote></td>
<td>N</td>
<td>%</td>
<td>N</td>
<td><blockquote>
<p>%</p>
</blockquote></td>
<td>N</td>
<td>%</td>
</tr>
<tr class="odd">
<td>475</td>
<td>(90)</td>
<td>163</td>
<td>(91)</td>
<td>39</td>
<td><blockquote>
<p>(93)</p>
</blockquote></td>
<td>457</td>
<td>(88)</td>
<td><blockquote>
<p>141</p>
</blockquote></td>
<td><blockquote>
<p>(83)</p>
</blockquote></td>
<td>25</td>
<td>(74)</td>
</tr>
<tr class="even">
<td>Clinical AE</td>
<td>461</td>
<td>(88)</td>
<td>159</td>
<td>(89)</td>
<td>39</td>
<td><blockquote>
<p>(93)</p>
</blockquote></td>
<td>435</td>
<td>(84)</td>
<td><blockquote>
<p>138</p>
</blockquote></td>
<td><blockquote>
<p>(81)</p>
</blockquote></td>
<td>24</td>
<td>(71)</td>
</tr>
<tr class="odd">
<td>Laboratory AE</td>
<td>167</td>
<td>(32)</td>
<td>49</td>
<td>(27)</td>
<td>13</td>
<td><blockquote>
<p>(31)</p>
</blockquote></td>
<td>141</td>
<td>(27)</td>
<td>37</td>
<td><blockquote>
<p>(22)</p>
</blockquote></td>
<td>5</td>
<td>(15)</td>
</tr>
<tr class="even">
<td>Fatal AE</td>
<td><strong>0</strong></td>
<td><strong>( 0)</strong></td>
<td><strong>5</strong></td>
<td><strong>( 3)</strong></td>
<td><strong>3</strong></td>
<td><blockquote>
<p><strong>( 7)</strong></p>
</blockquote></td>
<td><strong>0</strong></td>
<td><strong>( 0)</strong></td>
<td><strong>1</strong></td>
<td><blockquote>
<p><strong>( 1)</strong></p>
</blockquote></td>
<td><strong>0</strong></td>
<td><strong>( 0)</strong></td>
</tr>
<tr class="odd">
<td><p id="sae" class="heading">SAE</p></td>
<td><strong>31</strong></td>
<td><strong>( 6)</strong></td>
<td><strong>30</strong></td>
<td><strong>(17)</strong></td>
<td><strong>9</strong></td>
<td><blockquote>
<p><strong>(21)</strong></p>
</blockquote></td>
<td><strong>40</strong></td>
<td><strong>( 8)</strong></td>
<td><strong>20</strong></td>
<td><blockquote>
<p><strong>(12)</strong></p>
</blockquote></td>
<td><strong>5</strong></td>
<td><strong>(15)</strong></td>
</tr>
<tr class="even">
<td>AE leading to withdrawal</td>
<td><strong>23</strong></td>
<td><strong>( 4)</strong></td>
<td><strong>22</strong></td>
<td><strong>(12)</strong></td>
<td><strong>5</strong></td>
<td><blockquote>
<p><strong>(12)</strong></p>
</blockquote></td>
<td><strong>18</strong></td>
<td><strong>( 4)</strong></td>
<td><strong>11</strong></td>
<td><blockquote>
<p><strong>( 7)</strong></p>
</blockquote></td>
<td><strong>4</strong></td>
<td><strong>(12)</strong></td>
</tr>
<tr class="odd">
<td>AE leading to dose interruption</td>
<td><strong>67</strong></td>
<td><strong>(13)</strong></td>
<td><strong>36</strong></td>
<td><strong>(20)</strong></td>
<td><strong>11</strong></td>
<td><blockquote>
<p><strong>(26)</strong></p>
</blockquote></td>
<td><strong>64</strong></td>
<td><strong>(12)</strong></td>
<td><strong>22</strong></td>
<td><blockquote>
<p><strong>(13)</strong></p>
</blockquote></td>
<td><strong>6</strong></td>
<td><strong>(18)</strong></td>
</tr>
<tr class="even">
<td>AE leading to dose reduction</td>
<td>0</td>
<td>( 0)</td>
<td>0</td>
<td>( 0)</td>
<td>0</td>
<td><blockquote>
<p>( 0)</p>
</blockquote></td>
<td>0</td>
<td>( 0)</td>
<td>0</td>
<td><blockquote>
<p>( 0)</p>
</blockquote></td>
<td>0</td>
<td>(.0)</td>
</tr>
<tr class="odd">
<td>Severe or life-threatening/intractable AE</td>
<td>67</td>
<td>(13)</td>
<td>46</td>
<td>(26)</td>
<td>7</td>
<td><blockquote>
<p>(17)</p>
</blockquote></td>
<td>78</td>
<td>(15)</td>
<td>36</td>
<td><blockquote>
<p>(21)</p>
</blockquote></td>
<td>7</td>
<td>(21)</td>
</tr>
<tr class="even">
<td>At least possibly drug-related AE</td>
<td>282</td>
<td>(54)</td>
<td>94</td>
<td>(53)</td>
<td>17</td>
<td><blockquote>
<p>(41)</p>
</blockquote></td>
<td>223</td>
<td>(43)</td>
<td>57</td>
<td><blockquote>
<p>(34)</p>
</blockquote></td>
<td>8</td>
<td>(24)</td>
</tr>
<tr class="odd">
<td>Infection (serious and non-serious)</td>
<td>303</td>
<td>(58)</td>
<td>95</td>
<td>(53)</td>
<td>21</td>
<td><blockquote>
<p>(50)</p>
</blockquote></td>
<td>258</td>
<td>(50)</td>
<td>76</td>
<td><blockquote>
<p>(45)</p>
</blockquote></td>
<td>14</td>
<td>(41)</td>
</tr>
<tr class="even">
<td>Serious infection</td>
<td>7</td>
<td>(1)</td>
<td>11</td>
<td>( 6)</td>
<td>2</td>
<td><blockquote>
<p>( 5)</p>
</blockquote></td>
<td>4</td>
<td>( 1)</td>
<td>3</td>
<td><blockquote>
<p>( 2)</p>
</blockquote></td>
<td>1</td>
<td>(3)</td>
</tr>
<tr class="odd">
<td>Malignancy</td>
<td><strong>7</strong></td>
<td><strong>( 1)</strong></td>
<td><strong>3</strong></td>
<td><strong>( 2)</strong></td>
<td><strong>2</strong></td>
<td><blockquote>
<p><strong>( 5)</strong></p>
</blockquote></td>
<td><strong>1</strong></td>
<td><strong>( 0)</strong></td>
<td><strong>1</strong></td>
<td><blockquote>
<p><strong>( 1)</strong></p>
</blockquote></td>
<td><strong>0</strong></td>
<td><strong>( 0)</strong></td>
</tr>
<tr class="even">
<td>Immunologic reaction</td>
<td>5</td>
<td>( 1)</td>
<td>1</td>
<td>(1)</td>
<td>0</td>
<td><blockquote>
<p>( 0)</p>
</blockquote></td>
<td>4</td>
<td>( 1)</td>
<td>0</td>
<td><blockquote>
<p>( 0)</p>
</blockquote></td>
<td>0</td>
<td>( 0)</td>
</tr>
<tr class="odd">
<td colspan="13"><blockquote>
<p>Q2w = every other week sc = subcutaneous</p>
<p><sup>a</sup> More than one AE per patient possible.</p>
</blockquote></td>
</tr>
</tbody>
</table>

C.  **Other Adverse Events**

**Table 59** demonstrates the most frequently reported
treatment-emergent AEs, irrespective of relation to study drug, in
patients treated with adalimumab during placebo-controlled and
non-placebo-controlled study periods, by treatment received.

Table 59: ISS : Number (%) of patients with the most frequently reported
treatment-emergent AEs, irrespective of relation to study drug, in
patients treated with adalimumab during placebo-controlled and
non-placebo-controlled study periods, by treatment received -- all
studies in RA patients

+------------------+-------+-------+-------+------+---------+-------+
|                  | **    |       | **All |      | ### P   |       |
|                  | Adali |       | adali |      | lacebo- |       |
|                  | mumab |       | mumab |      | Treated |       |
|                  | 40 mg |       | d     |      |  Patien |       |
|                  | Q2w   |       | oses, |      | ts from |       |
|                  | sc**  |       | sc    |      |  the Ad |       |
|                  |       |       | and   |      | equate  |       |
|                  | **    |       | iv**  |      | and Wel |       |
|                  | (N=19 |       |       |      | l-Contr |       |
|                  | 03)** |       | **    |      | olled S |       |
|                  |       |       | (N=23 |      | tudies  |       |
|                  |       |       | 34)** |      | (N=690) |       |
+------------------+-------+-------+-------+------+---------+-------+
| **Body           | **N   | **E   | **N   | **E  | **N     | **E   |
| system/AE^b^**   | (%)** | (E/   | (%)** | (E/1 | (%)**   | (E/   |
|                  |       | 100** |       | 00** |         | 100** |
|                  |       |       |       |      |         |       |
|                  |       | *     |       | **p  |         | *     |
|                  |       | *pt-y |       | t-yr |         | *pt-y |
|                  |       | rs)** |       | s)** |         | rs)** |
+------------------+-------+-------+-------+------+---------+-------+
| **Abdominal      | 111   | 130   | 222   | 276  | 30 (4)  | 32    |
| pain**           | (6)   | (8)   | (10)  | (9)  |         | (9)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Accidental     | 183   | 221   | 309   | 396  | 56 (8)  | 59    |
| Injury**         | (10)  | (14)  | (13)  | (13) |         | (16)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Asthenia**     | 104   | 114   | 224   | 269  | 40 (6)  | 41    |
|                  | (6)   | (7)   | (10)  | (9)  |         | (11)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Back pain**    | 128   | 140   | 244   | 325  | 25 (4)  | 29    |
|                  | (7)   | (9)   | (11)  | (11) |         | (8)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Clinical flare | 248   | 306   | 406   | 600  | 75 (11) | 89    |
| reaction**       | (13)  | (20)  | (17)  | (20) |         | (25)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Fever**        | 42    | 48    | 164   | 239  | 17 (3)  | 18    |
|                  | (2)   | (3)   | (7)   | (8)  |         | (5)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Flu syndrome** | 132   | 148   | 279   | 392  | 41 (6)  | 43    |
|                  | (7)   | (10)  | (12)  | (13) |         | (12)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Infection**    | 62    | 63    | 131   | 145  | 13 (2)  | 14    |
|                  | (3)   | (4)   | (6)   | (5)  |         | (4)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Surgery**      | 108   | 122   | 208   | 270  | 23 (3)  | 25    |
|                  | (6)   | (8)   | (9)   | (9)  |         | (7)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Hypertension** | 99    | 106   | 218   | 287  | 18 (3)  | 18    |
|                  | (5)   | (7)   | (9)   | (10) |         | (5)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Diarrhea**     | 132   | 163   | 257   | 350  | 66 (10) | 86    |
|                  | (7)   | (11)  | (11)  | (12) |         | (24)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Nausea**       | 134   | 158   | 265   | 350  | 54 (8)  | 63    |
|                  | (7)   | (10)  | (11)  | (12) |         | (17)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Sore throat**  | 98    | 124   | 190   | 244  | 39 (6)  | 45    |
|                  | (5)   | (8)   | (8)   | (8)  |         | (14)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Decreased      | **191 | **238 | **524 | **   | **44    | **49  |
| hemoglobin**     | (     | (     | (     | 1077 | (6)**   | (     |
|                  | 10)** | 15)** | 23)** | (3   |         | 14)** |
|                  |       |       |       | 7)** |         |       |
+------------------+-------+-------+-------+------+---------+-------+
| **Injection site | **122 | **388 | **250 | *    | **85    | **330 |
| pain**           | (6)** | (     | (     | *726 | (12)**  | (     |
|                  |       | 25)** | 11)** | (2   |         | 91)** |
|                  |       |       |       | 5)** |         |       |
+------------------+-------+-------+-------+------+---------+-------+
| **Injection site | **104 | **210 | **195 | *    | **8     | **9   |
| reaction**       | (6)** | (     | (8)** | *373 | (1)**   | (3)** |
|                  |       | 14)** |       | (1   |         |       |
|                  |       |       |       | 3)** |         |       |
+------------------+-------+-------+-------+------+---------+-------+
| **BUN            | 150   | 194   | 274   | 532  | 23 (3)  | 32    |
| increased**      | (8)   | (13)  | (12)  | (18) |         | (9)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Peripheral     | 83    | 97    | 144   | 176  | 24 (4)  | 27    |
| edema**          | (4)   | (6)   | (6)   | (6)  |         | (8)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Arthralgia**   | 84    | 92    | 185   | 228  | 43 (6)  | 48    |
|                  | (4)   | (6)   | (8)   | (8)  |         | (13)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Joint          | 100   | 114   | 201   | 250  | 40 (6)  | 43    |
| disorder**       | (5)   | (7)   | (9)   | (9)  |         | (12)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Dizziness**    | 75    | 91    | 159   | 228  | 32 (5)  | 36    |
|                  | (4)   | (6)   | (7)   | (8)  |         | (10)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Headache**     | 175   | 245   | 387   | 646  | 53 (8)  | 67    |
|                  | (9)   | (16)  | (17)  | (22) |         | (19)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Depression**   | 70    | 74    | 116   | 129  | 22 (3)  | 27    |
|                  | (4)   | (5)   | (5)   | (4)  |         | (8)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Bronchitis**   | 116   | 133   | 242   | 324  | 35 (5)  | 42    |
|                  | (6.1) | (9)   | (10)  | (11) |         | (12)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Cough          | 109   | 127   | 242   | 294  | 42 (6)  | 45    |
| increased**      | (5.7) | (8)   | (10)  | (10) |         | (12)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Rhinitis**     | 280   | 376   | 533   | 858  | 93 (14) | 106   |
|                  | (15)  | (24)  | (23)  | (29) |         | (29)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Sinusitis**    | 178   | 234   | 275   | 389  | 61 (9)  | 78    |
|                  | (9)   | (15)  | (12)  | (13) |         | (22)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Upper          | 294   | 373   | 430   | 585  | 86 (13) | 96    |
| respiratory      | (15)  | (24)  | (18)  | (20) |         | (27)  |
| infection**      |       |       |       |      |         |       |
+------------------+-------+-------+-------+------+---------+-------+
| **Herpes         | 65    | 77    | 131   | 183  | 15 (2)  | 21    |
| simplex**        | (3)   | (5)   | (6)   | (6)  |         | (6)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Pruritus**     | 72    | 80    | 237   | 310  | 10 (1)  | 11    |
|                  | (4)   | (5)   | (10)  | (11) |         | (3)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Rash**         | 205   | 237   | 432   | 600  | 43 (6)  | 49    |
|                  | (11)  | (15)  | (19)  | (20) |         | (14)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Skin           | 77    | 86    | 172   | 215  | 20 (3)  | 23    |
| disorder**       | (4)   | (6)   | (7)   | (7)  |         | (6)   |
+------------------+-------+-------+-------+------+---------+-------+
| **Hematuria**    | 47    | 58    | 241   | 424  | 28 (4)  | 41    |
|                  | (3)   | (4)   | (10)  | (14) |         | (11)  |
+------------------+-------+-------+-------+------+---------+-------+
| **Urinary tract  | 129   | 160   | 195   | 251  | 36 (5)  | 50    |
| infection**      | (7)   | (10)  | (8)   | (9)  |         | (14)  |
+------------------+-------+-------+-------+------+---------+-------+
| Q2w = every      |       |       |       |      |         |       |
| other week sc =  |       |       |       |      |         |       |
| subcutaneous iv  |       |       |       |      |         |       |
| = intravenous    |       |       |       |      |         |       |
|                  |       |       |       |      |         |       |
| ^a^ Occurring in |       |       |       |      |         |       |
| 5% of patients  |       |       |       |      |         |       |
| in the "all      |       |       |       |      |         |       |
| adalimumab"      |       |       |       |      |         |       |
| treatment group. |       |       |       |      |         |       |
+------------------+-------+-------+-------+------+---------+-------+

D.  **Deaths and Comparable Mortality Rates**

Eight patients, 7 treated with adalimumab and 1 treated with placebo
died, as a result of AEs during the adequate and well-controlled
studies; the primary AE leading to death is presented by patient in
Table 60. Deaths occurred at a rate of 0.3/100 patient-years (CI, 0.26,
0.82) among placebo-treated patients, 0.9/100 patient-years (CI, 0.23,
1.55) among all adalimumab-treated patients, and 1.3/100 patient-years
(CI, 0.16, 2.35) among patients receiving the proposed recommended dose.
Two additional deaths among adalimumab-treated patients (total of 9) are
provided in supplementary final safety updates: 1.) diverticulitis with
secondary sepsis and 2.) hepatic necrosis. The most frequent causes of
death were sepsis (3) and malignancy (3) \[carcinoma (2) and lymphoma
(1)\]. Two deaths related to infection are described in greater detail
in Table 61.

Table 60 : ISS : Patients with fatal AEs -- Adequate and Well-Controlled
Studies

![](media/image33.png){width="6.010416666666667in"
height="2.6458333333333335in"}

Table 61 : Deaths Related to Infections

  ----------- ---------------- -----------------------------------------------
  **Patient   **Adverse        **Relevant Medical History**
  Number**    Event**          

  8702        Urosepsis &      Onset fatigue and disturbance of equilibrium
              septic shock     (incoordination), patient was withdrawn from
                               study, and event resolved. Patient became
                               febrile with urinary incontinence and a week
                               later developed a urinary tract infection and a
                               upper respiratory infection. Urosepsis (E.
                               coli) was followed by septic shock and
                               pancytopenia, cardiac arrest and death.

  15106       Herpes zoster,   Herpes zoster with dissemination, necrotizing
              dissemination,   fasciitis of upper extremity, superinfection
              superinfection   with Group A streptococcus and death.
  ----------- ---------------- -----------------------------------------------

Table 62 lists all 22 fatal adverse events from among all patients
treated with adalimumab in the clinical development program. Two
additional deaths (total of 24), one each from diverticulitis with
associated sepsis and hepatic necrosis are not shown on this table. Even
though the majority (77%) of patients enrolled in these studies were
females, the majority of deaths occurred in male subjects (58%
\[14/24\]). The major categories for the deaths include cardiovascular
(7), malignancy (6), infections (5), and gastrointestinal (3),
\[including the additional death from diverticulitis and associated
sepsis not shown on this Table\].

Table 62 : ISS : List of fatal adverse events during treatment with
adalimumab. All patients treated with adalimumab. Study group: all
studies in patients with RA (DE001/3, 004, 005/X, 010, 007, 009/X, 011,
019, 031, 018, 020).

![](media/image34.wmf)

Because the adalimumab safety database includes a significant number of
older patients, including a substantial portion aged 65 to 75 (22%) and
over age 75 (5%), some deaths are expected. In addition, mortality has
been reported to be increased in RA patients. To determine whether the
death rate was higher than expected, the observed rate was compared to
that expected among various populations (Table 63). Standardized
Mortality Rate (SMR - ratio of observed death rate compared to age
adjusted expected frequency) was 0.72 for all adalimumab-treated
subjects (C.I., 0.46, 1.05), 1.38 for males (C.I., 0.72, 2.44) and 0.45
for females (C.I., 0.22, 0.83). The confidence interval for the male
deaths overlaps 'one,' implying that the mortality rate observed was
within the expected range. The mortality rate for the females was lower
than expected. The SMR for adalimumab-treated patients did not exceed
that observed in a variety of epidemiologic studies of RA patients

Table 63 : ISS : Comparable Mortality Rates Among RA Patients

+----------------------+--------------------------------+-------------+
| Study                | Population Base                | SMR\*       |
|                      |                                |             |
|                      |                                | (95% CI)    |
+----------------------+--------------------------------+-------------+
| Wolfe et al (1994)   | Tertiary referral center       | 1.98 - 3.08 |
| [^1]                 |                                |             |
|                      | (North America                 |             |
+----------------------+--------------------------------+-------------+
|                      | Community-based (North         | 1.98        |
|                      | America)                       |             |
+----------------------+--------------------------------+-------------+
| Symmons et al (1998) | Hospital-based referral center | 2.7         |
| [^2]                 | (England)                      |             |
|                      |                                | (2.4, 3.1)  |
+----------------------+--------------------------------+-------------+
| Gabriel et al (1999) | RA patients (All Rochester)    | 1.38        |
| [^3]                 |                                |             |
|                      |                                | (1.22,      |
|                      |                                | 1.55)       |
+----------------------+--------------------------------+-------------+
| Krause et al (2000)  | Methotrexate responders        | 1.47        |
| [^4]                 |                                |             |
+----------------------+--------------------------------+-------------+
|                      | Methotrexate non-responders    | 4.11        |
+----------------------+--------------------------------+-------------+
| Adalimumab           | Calculation using WHO          | 0.72        |
|                      | mortality rates                |             |
| clinical             |                                | (0.46,      |
|                      | (22 adalimumab-treated         | 1.05)       |
| development          | patients                       |             |
|                      |                                |             |
| program              | that died)                     |             |
+----------------------+--------------------------------+-------------+
|                      | Males (13)                     | 1.38        |
|                      |                                |             |
|                      |                                | (0.72,      |
|                      |                                | 2.44)       |
+----------------------+--------------------------------+-------------+
|                      | Females (9)                    | 0.45        |
|                      |                                |             |
|                      |                                | (0.22,      |
|                      |                                | 0.83)       |
+----------------------+--------------------------------+-------------+

\* Standardized Mortality Rate

Highest mortality rates associated with increased age, male sex, RF
positivity, and continued signs of active inflammation

E. Serious Adverse Events

Overall the rate of SAEs was not higher among adalimumab-treated
patients compared to placebo controls at the proposed recommended dose
(Table 56). However, a higher rate of SAEs was observed among patients
receiving 40 mg weekly.

To explore why SAEs were more frequent among patients receiving 40 mg
weekly, the individual studies were examined. All 103 patients receiving
that dose were in study DE011, the European monotherapy study. In that
study, the rate of SAEs was lower among patients receiving adalimumab 40
mg weekly (22.6/100 patient--years) or adalimumab 40 mg biweekly
(26.0/100 patient--years) than those receiving placebo (39.7/100
patient--years) \[Table 64\]. Thus, the rate of SAEs does not appear to
be increased in patients receiving adalimumab 40 mg weekly.

For both adalimumab- and placebo-treated patients, the percentage of
patients reporting SAEs was higher among patients 65 years of age than
among patients \<65 years of age, and higher still among the small group
of patients 75 years of age (Table 95). Within each age group the
overall percentage of SAEs was slightly higher among adalimumab-treated
patients than among controls. DDuring the double-blin,
placebo-controlled periods of the adequate and well-controlled studies,
151 adalimumab-treated patients (11% of 1380; 19 patient /100 pt-yrs)
and 60 placebo-treated patients (9% of 690 ; 17 patients/100 pt-yrs)
experienced one or more SAEs. SAEs reported slightly more frequently by
adalimumab-treated patients included surgery, clinical flare reaction,
bone fracture, and pneumonia.

The most commonly reported SAE was surgery, a HARTS term that
encompassed arthroplasty and arthrodesis procedures (18 events in 17
patients), tendon repair, hernia repair, aneurysm repair, uterine
prolapse repair, removal of fibroids, cholecystectomy, pacer placement
revision, prostatectomy, and removal of a basal cell carcinoma (one
patient each). Each of the five most commonly reported SAEs occurred
more often among all adalimumab- than among placebo-treated patients.
Ten percent of adalimumab-treated patients and 8 % of placebo-treated
patients experiencd one or more SAEs other than planned surgeries

For both adalimumab- and placebo-treated patients, the percentage of
patients reporting SAEs was not higher among patients taking
corticosteroids at baseline than among patients not taking
corticosteroids at baseline, and was not higher among patients taking
concomitant MTX than among patients who were not (Table 97).

Table 64 : Study DE011 : Overview of number (%) of patients with
treatment-emergent AEs (safety set)

+-----------------------------+-----+-----+-----+-----+------+--------+
|                             | **  |     |     |     | **P  |        |
|                             | Ada |     |     |     | lace |        |
|                             | lim |     |     |     | bo** |        |
|                             | uma |     |     |     |      |        |
|                             | b** |     |     |     |      |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
|                             | *   |     | *   |     |      |        |
|                             | *40 |     | *40 |     |      |        |
|                             | mg  |     | mg  |     |      |        |
|                             | Q2  |     | Q2  |     |      |        |
|                             | w** |     | w** |     |      |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
|                             | *   |     | *   |     | **4  |        |
|                             | *50 |     | *48 |     | 0.34 |        |
|                             | .07 |     | .61 |     | pt-y |        |
|                             | pt  |     | pt  |     | rs** |        |
|                             | -yr |     | -yr |     |      |        |
|                             | s** |     | s** |     |      |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
|                             | **  |     | **  |     | **(  |        |
|                             | (N= |     | (N= |     | N=11 |        |
|                             | 113 |     | 103 |     | 0)** |        |
|                             | )** |     | )** |     |      |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
|                             | N   | N/  | N   | N/  | N    | N/100  |
|                             | (%) | 100 | (%) | 100 | (%)  |        |
|                             |     |     |     |     |      | pt-yrs |
|                             |     | pt- |     | pt- |      |        |
|                             |     | yrs |     | yrs |      |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **Patients with any AE      | 112 | 22  | 102 | 20  | 105  | 260.3  |
| ^a^**                       | (99 | 3.7 |     | 9.9 |      |        |
|                             | .1) |     | (99 |     | (9   |        |
|                             |     |     | .0) |     | 5.5) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **Serious AE (SAE)**        | 13  | **  | 11  | **  | 16   | **     |
|                             |     | 26. |     | 22. |      | 39.7** |
|                             | (11 | 0** | (10 | 6** | (1   |        |
|                             | .5) |     | .7) |     | 4.5) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **Severe or                 | 27  | 5   | 21  | 4   | 25   | 62.0   |
| l                           |     | 3.9 |     | 3.2 |      |        |
| ife-threatening/intractable | (23 |     | (20 |     | (2   |        |
| AE**                        | .9) |     | .4) |     | 2.7) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **At least possibly drug-   | 74  | 14  | 69  | 14  | 49   | 121.5  |
| related AE**                |     | 7.8 |     | 2.0 |      |        |
|                             | (65 |     | (67 |     | (4   |        |
|                             | .5) |     | .0) |     | 4.5) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **AE leading to death**     | 2   | 4.0 | 1   | 2.1 | 1    | 2.5    |
|                             |     |     |     |     |      |        |
|                             | (1  |     | (1  |     | (    |        |
|                             | .8) |     | .0) |     | 0.9) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **AE leading to permanent   | 7   | 1   | 5   | 1   | 3    | 7.4    |
| withdrawal**                |     | 4.0 |     | 0.3 |      |        |
|                             | (6  |     | (4  |     | (    |        |
|                             | .2) |     | .9) |     | 2.7) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **AE leading to temporary   | 15  | 3   | 15  | 3   | 4    | 9.9    |
| withdrawal**                |     | 0.0 |     | 0.9 |      |        |
|                             | (13 |     | (14 |     | (    |        |
|                             | .3) |     | .6) |     | 3.6) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **AE leading to dose        | 0   | 0.0 | 0   | 0.0 | 0    | 0.0    |
| reduction**                 |     |     |     |     |      |        |
|                             | (0  |     | (0  |     | (    |        |
|                             | .0) |     | .0) |     | 0.0) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **AE leading to dose        | 0   | 0.0 | 0   | 0.0 | 0    | 0.0    |
| increase**                  |     |     |     |     |      |        |
|                             | (0  |     | (0  |     | (    |        |
|                             | .0) |     | .0) |     | 0.0) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **AE leading to switch to   | 4   | 8.0 | 0   | 0.0 | 11   | 27.3   |
| rescue period**             |     |     |     |     |      |        |
|                             | (3  |     | (0  |     | (1   |        |
|                             | .5) |     | .0) |     | 0.0) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **Infection**               | 56  | 11  | 50  | 10  | 43   | 106.6  |
|                             |     | 1.8 |     | 2.9 |      |        |
|                             | (49 |     | (48 |     | (3   |        |
|                             | .6) |     | .5) |     | 9.1) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **Serious infection**       | 1   | 2.0 | 2   | 4.1 | 0    | 0.0    |
|                             |     |     |     |     |      |        |
|                             | (0  |     | (1  |     | (    |        |
|                             | .9) |     | .9) |     | 0.0) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **Malignancy**              | 2   | 4.0 | 1   | 2.1 | 1    | 2.5    |
|                             |     |     |     |     |      |        |
|                             | (1  |     | (1  |     | (    |        |
|                             | .8) |     | .0) |     | 0.9) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **Immunologic reaction**    | 1   | 2.0 | 1   | 2.1 | 0    | 0.0    |
|                             |     |     |     |     |      |        |
|                             | (0  |     | (1  |     | (    |        |
|                             | .9) |     | .0) |     | 0.0) |        |
+-----------------------------+-----+-----+-----+-----+------+--------+
| **^a^** More than one AE    |     |     |     |     |      |        |
| per patient possible.       |     |     |     |     |      |        |
+-----------------------------+-----+-----+-----+-----+------+--------+

F. Malignancies and Comparative Expected Incidence Rates

Eight malignancies (excluding non-melanoma skin cancers) were observed
in adalimumab-treated patients within the adequate and well controlled
studies, and none were observed among placebo-treated patients. Thirty
malignancies (excluding non-melanoma skin cancers) were observed in
adalimumab-treated patients within the clinical development program, and
none were observed among placebo-treated patients (Table 65). Six
patients died of their malignancies. Adalimumab-treated patients had
approximately an eight-fold greater safety observational exposure in the
studies than did placebo-treated patients. Matching the data from the
SEER database to the age and sex distribution seen in all patients
treated with adalimumab, the expected number of2 cancers dwas 22.

In the clinical development program, based on this smaller initial
database, a higher SIR rate for malignancies was suggested (Table 65).

Table 65 : ISS : Malignancies in the Clinical Development Program

+----------------+-----------+----------+-------------+--------------+
|                | M         |          | SIR         | Exposure     |
|                | alignancy |          | (S          |              |
|                | incidence |          | tandardized | (pa          |
|                |           |          | Incidence   | tient-years) |
|                |           |          | Ratio)      |              |
|                |           |          |             |              |
|                |           |          | \[95% CI\]  |              |
+----------------+-----------+----------+-------------+--------------+
|                | Observed  | Expected |             |              |
|                | incidence |          |             |              |
|                |           | I        |             |              |
|                |           | ncidence |             |              |
|                |           | ^1^      |             |              |
+----------------+-----------+----------+-------------+--------------+
| Adequate and   |           |          |             |              |
| W              |           |          |             |              |
| ell-Controlled |           |          |             |              |
| Studies        |           |          |             |              |
+----------------+-----------+----------+-------------+--------------+
| Malignancies   | 8         | 6        |             |              |
| in             |           |          |             |              |
| adal           |           |          |             |              |
| imumab-treated |           |          |             |              |
+----------------+-----------+----------+-------------+--------------+
| Malignancies   | 0         | 0.8      |             |              |
| in             |           |          |             |              |
| p              |           |          |             |              |
| lacebo-treated |           |          |             |              |
+----------------+-----------+----------+-------------+--------------+
| Clinical       |           |          |             |              |
| Development    |           |          |             |              |
| Program        |           |          |             |              |
+----------------+-----------+----------+-------------+--------------+
| Malignancies   | 30        | 22       | 1.33        | 2,954        |
| in             |           |          |             |              |
| adal           |           |          | \[0.9,      |              |
| imumab-treated |           |          | 1.9\]       |              |
+----------------+-----------+----------+-------------+--------------+
| Malignancies   | 0         | 2.9      |             | 385          |
| in             |           |          |             |              |
| p              |           |          |             |              |
| lacebo-treated |           |          |             |              |
+----------------+-----------+----------+-------------+--------------+

> ^1^ Matching data from NCI SEER database to calculate expected
> age-matched malignancy rate
>
> for US population (SEER Program Public-Use Data 1973-1998)

These thirty malignancies (excluding non-melanoma skin cancers) were
observed among 2334 adalimumab-treated patients over a median of 12
months during the clinical development program and were submitted with
the BLA. The most frequently seen malignancies were breast (4), prostate
(4), gastrointestinal (4), non-Hodgkin's lymphoma (4),
uterine/endometrial (3), and melanoma (2) \[Table 66\].

Thirty-six non-melanoma skin cancers and 48 malignancies of various
types were observed in 2468 RA patients treated in clinical trials with
adalimumab for a median of 24 months and were submitted with the final
safety update through August 31, 2002. The malignancies observed during
use of adalimumab were neoplasms of the immune system (9), breast (7),
colon-rectum (6), uterine-cervical (5), prostate (5), melanoma (3),
gallbladder-bile ducts (2), and other carcinomas.

Table 66 : ISS : Cancer Incidence Analysis in Clinical Development
Program

+------------------+----------------+----------------+----------------+
| **Cancer Site**  | **Observed in  | **Observed     | **Observed     |
|                  | BLA ^1^**      | in**           | in**           |
|                  |                |                |                |
|                  |                | **Interim**    | **Final Safety |
|                  |                |                | Update ^3^**   |
|                  |                | **Safety       |                |
|                  |                | Update ^2^**   |                |
+------------------+----------------+----------------+----------------+
| **Exposure**     | **2334         | **2467         | **2468         |
|                  | patients**     | patients**     | patients**     |
|                  |                |                |                |
|                  | **median**     | **median**     | **median**     |
|                  |                |                |                |
|                  | **12 months**  | **19.3         | **24 months**  |
|                  |                | months**       |                |
+------------------+----------------+----------------+----------------+
| **All Sites**    | **30**         | **38**         | **48**         |
+------------------+----------------+----------------+----------------+
| **All            | **4**          | **8**          | **10**         |
| lymphomas**      |                |                |                |
+------------------+----------------+----------------+----------------+
| **NHL**          |                | **7**          |                |
+------------------+----------------+----------------+----------------+
| **Hodgkin's D**  |                | **1**          |                |
+------------------+----------------+----------------+----------------+
| **Breast**       | **4**          | **5**          | 7              |
+------------------+----------------+----------------+----------------+
| **Colon --       | **3**          | **4**          | **6**          |
| rectum**         |                |                |                |
+------------------+----------------+----------------+----------------+
| **Cervix --      | **3**          | **3**          | **5**          |
| Uteri**          |                |                |                |
+------------------+----------------+----------------+----------------+
| **Prostate**     | **4**          | **4**          | **5**          |
+------------------+----------------+----------------+----------------+
| **Melanoma**     | **2**          | **2**          | **3**          |
+------------------+----------------+----------------+----------------+
| **Gallbladder    | **1**          |                | **2**          |
| --**             |                |                |                |
|                  |                |                |                |
| **bile ducts**   |                |                |                |
+------------------+----------------+----------------+----------------+
| **               | **2**          |                | **2**          |
| Adenocarcinoma** |                |                |                |
|                  |                |                |                |
| **(unknown       |                |                |                |
| origin)**        |                |                |                |
+------------------+----------------+----------------+----------------+
| **Other**        | **7**          | **11**         | **8**          |
+------------------+----------------+----------------+----------------+
| **Non-melanoma   | **24**         | **32**         | **36**         |
| skin cancers**   |                |                |                |
+------------------+----------------+----------------+----------------+
| **Basal cell**   |                | **23**         |                |
+------------------+----------------+----------------+----------------+
| **Squamous       |                | **9**          |                |
| cell**           |                |                |                |
+------------------+----------------+----------------+----------------+

> 1 Data available through August 31, 2001
>
> 2 Data available through March 29, 2002
>
> ^3^ Data available through August 31, 2002

Based on 46 of the 48 malignancies observed in the final safety update,
for which data was available to up-date the observed Standardized
Incidence Ratio (SIR), the observed SIR (ratio of observed rate to
age-adjusted expected frequency) for malignancies was 1.00 (95% CI, 0.7,
1.3)\] \[Table 67\], implying that the observed frequency of
malignancies among adalimumab-treated patients was within the expected
incidence range.

Table 67: ISS : Comparative Expected Cancer Incidence Rates In the
Adalimumab Clinical Development Program Through August 31, 2002

+----------------------+----------+---------+---------+---------------+
| **Cancer Type** \*   | **Ob     | **Exp   | **SIR** | **95% CI**    |
|                      | served** | ected** |         |               |
+----------------------+----------+---------+---------+---------------+
| **All Sites**        | 46       | 45.82   | 1.00    | (0.7 -- 1.3)  |
+----------------------+----------+---------+---------+---------------+
| #### All Lymphomas   | 10       | 1.85    | 5.42    | (2.6 -- 10.0) |
+----------------------+----------+---------+---------+---------------+
| **NHL**              | 9        | 1.70    | 5.28    | (2.4 --10.0)  |
+----------------------+----------+---------+---------+---------------+
| **Hodgkin's          | 1        | 0.14    | 7.09    | (0.1 -- 39.5) |
| Disease**            |          |         |         |               |
+----------------------+----------+---------+---------+---------------+
| **Breast**           | 7        | 11.15   | 0.63    | (0.3 -- 1.3)  |
+----------------------+----------+---------+---------+---------------+
| **Colon**            | 5        | 4.75    | 1.05    | (0.3 -- 2.5)  |
+----------------------+----------+---------+---------+---------------+
| **Lung**             | 1        | 6.67    | 0.15    | (0.0 -- 0.8)  |
+----------------------+----------+---------+---------+---------------+
| **Melanoma**         | 3        | 1.53    | 1.97    | (0.4 -- 5.7)  |
+----------------------+----------+---------+---------+---------------+
| **Prostate**         | 5        | 4.45    | 1.12    | (0.4 -- 2.6)  |
+----------------------+----------+---------+---------+---------------+
| **Uterine**          | 4        | 2.30    | 1.74    | (0.5 -- 4.4)  |
+----------------------+----------+---------+---------+---------------+
| **Other sites**      | 11       | 13.12   | 0.84    | (0.4 -- 1.5)  |
+----------------------+----------+---------+---------+---------------+
| #### Non-Melano      |          |         |         |               |
| ma Skin Cancers \*\* |          |         |         |               |
+----------------------+----------+---------+---------+---------------+
| #### Basal Cell      | 23       | 20.12   | 1.14    | (0.7 -- 1.7)  |
+----------------------+----------+---------+---------+---------------+
| **Squamous Cell**    | 9        | 3.79    | 2.37    | (1.1 -- 4.5)  |
+----------------------+----------+---------+---------+---------------+

> \* Cancer rates used were 1992-1999 SEER rates

\*\* Skin cancer rates used were 1977-1978 NCI study rates

A total of ten lymphomas, primarily Non Hodgkin's lymphoma, were
observed in patients treated with adalimumab. Based on these patients,
the observed SIR (ratio of observed rate to age-adjusted expected
frequency) for all lymphomas was 5.4 (95% CI, 2.6, 10.0). The wide
confidence interval seen for Non Hodgkin's lymphoma did not allow an
accurate determination of whether its frequency was greater than
expected. An attempt was made to correlate the onset of the lymphomas
and the duration of therapy with adalimumab. Analysis of the exposure
interval between initiation of adalimumab treatment and time-to-onset of
lymphoma did not provide clear evidence of a relationship between longer
duration-of-therapy and incidence of lymphoma (Table 68).

Table 68 : ISS : Lymphoma Incidence Rates by Duration of Treatment with
Adalimumab

+-----------------------+-----------------------+-----------------------+
| **Exposure Interval   | **Number/Total (%)**  | **N(N/100             |
| Until**               |                       | patient-years)**      |
|                       |                       |                       |
| **Time of Event -     |                       |                       |
| Months**              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0 - \< 6              | 2/2468 (0.08)         | 2 (0.2)               |
+-----------------------+-----------------------+-----------------------+
| 6 -\< 12              | 1/2216 (0.05)         | 1 (0.1)               |
+-----------------------+-----------------------+-----------------------+
| 12 - \<18             | 1/1867 (0.05)         | 1 (0.1)               |
+-----------------------+-----------------------+-----------------------+
| 18 - \< 24            | 2/1395 (0.14)         | 2 (0.4)               |
+-----------------------+-----------------------+-----------------------+
| 24 - \< 30            | 1/619 (0.16)          | 1 (0.4)               |
+-----------------------+-----------------------+-----------------------+
| 30 - \< 36            | 0/375 (0.00)          | 0 (0.0)               |
+-----------------------+-----------------------+-----------------------+
| 36 - \< 42            | 0/321 (0.31)          | 1 (0.8)               |
+-----------------------+-----------------------+-----------------------+

**Table 69** summarizes the cases of lymphoma observed during the
adalimumab clinical development program by type and concomitant therapy.
Lymphomas that have occurred in the setting of impaired immune function
have most often been large B cell, Non Hodgkin's lymphomas.[^5]
Similarly, the lymphoma type most often reported in this clinical
development program was the large B cell, Non Hodgkin's lymphoma. Ninety
percent of the lymphoma patients had received MTX (seven were receiving
concomitant MTX and two had received prior MTX), and 80% were receiving
concomitant corticosteroids.

Table 69 : ISS : Summary of Lymphoma Cases By Type and Concomitant
Therapy

+------------+-------------+----------+----------------+------+-------+
| **Subje    | **Type of   | **Family | **Concomitant  |      |       |
| ct/Study** | Lymphoma**  | H        | Therapy**      |      |       |
|            |             | istory** |                |      |       |
+------------+-------------+----------+----------------+------+-------+
|            |             |          | **A            | **M  | **C   |
|            |             |          | zathioprine/** | TX** | STD** |
|            |             |          |                |      |       |
|            |             |          | **Cycl         |      |       |
|            |             |          | ophosphamide** |      |       |
+------------+-------------+----------+----------------+------+-------+
| 2204/DE007 | Mantle zone | Sister-  |                | X    | X     |
|            | B cell      | leukemia |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 69/DE001   | Diffuse     |          |                | X    |       |
|            | Large B     |          |                | ^P^  |       |
|            | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1414/DE011 | MALT cell B |          | X ^P^          | X    | X     |
|            | cell        |          |                | ^P^  |       |
+------------+-------------+----------+----------------+------+-------+
| 8911/DE019 | Follicular  |          |                | X    |       |
|            | B cell      |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1          | Large B     |          |                |      | X     |
| 0509?DE031 | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1705/De019 | Mixed small |          |                | X    |       |
|            | and large B |          |                |      |       |
|            | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1          | T cell      |          |                | X    | X     |
| 1601/DE031 |             |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 8208/DE019 | Small and   |          |                | X    | X     |
|            | large B     |          |                |      |       |
|            | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1          | Large B     |          |                | X    | X     |
| 4605/DE031 | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 4404/DE019 | Hodgkin's   |          |                | X    | X     |
+------------+-------------+----------+----------------+------+-------+
| Total = 10 |             | 1        | 1              | 9    | 8     |
+------------+-------------+----------+----------------+------+-------+

P = previous

Among non- melanoma skin cancers, squamous cell carcinomas also occurred
at a frequency greater than expected (Table 67). However, the data used
to establish the expected rate were from 1977-1978, leading to some
uncertainty of the comparison.

The Kaplan Meier plot in Figure 14 shows that the rate of detection of
new malignancies (based on the August 31, 2001 data) was constant over
the observation period for all patients treated with adalimumab. The
plot does not support an association between increased development of
malignancy and longer duration of exposure to adalimumab. If the risk
had increased over time, the slope of the curve would become
increasingly negative with time. Longer duration of observation will be
required to determine whether exposure beyond 2 to 3 years is associated
with a higher risk of malignancy.

Figure 14 : ISS : Kaplan Meier curve of time to first malignancy during
treatment with adalimumab in all patients treated with adalimumab

> ![](media/image35.png){width="5.208333333333333in"
> height="2.8645833333333335in"}

In this clinical development program malignancies were observed at
frequency rates approximating the expected rate, except for neoplasms of
the immune system which were observed at a greater rate than expected.
Since the introduction of TNF blocking agents which affect host defenses
by modulating cellular immune responses, a major concern of the Agency
has been the possibility of an increased risk of development of
lymphomas among patients treated with TNF blocking agents. Published
literature suggests that RA patients with highly active disease have a
greater risk of lymphomas. Two published epidemiologic studies of 11,683
[^6] and 1,767 [^7] patients observed an approximately 4 to 5 fold
increased incidence of lymphoma in patients with moderately active RA.
The RA patients who participated in this clinical development program
all had moderate to severe RA with mean duration of disease above 10
years.

Available data are insufficient to determine whether adalimumab
increases the incidence of lymphomas above that expected in this patient
population. Continued monitoring of adalimumab-treated patients is
necessary to quantify the role of adalimumab, if any, in contributing to
the high observed incidence of lymphomas.

**G.** **Serious Infections**

Since the introduction of TNF blocking agents like adalimumab that
modulate cellular immunity, development of serious infections among
patients treated with anti-TNF agents has been a major concern of the
Agency. In the adalimumab clinical development program, serious
infections were defined as infections associated with hospitalization or
with use of parenteral antibiotics. Forty-one patients (34 \[3%\] of
1380 adalimumab-treated patients \[4.3 patients/100 pt-yrs\] and 7
\[1%\] of 690 placebo-treated patients \[1.9 patients/100 pt-yrs\])
experienced serious infections, as provided in the BLA data available
through Aug 31, 2001. Four adalimumab-treated patients experienced two
serious infections each; the remaining 37 patients experienced a single
serious infection. Two patients died of infectious AEs, and 13 patients
withdrew from the studies as a result of serious infections. The most
common organs involved in the infections were the respiratory, skin,
musculoskeletal, gastrointestinal, and genitourinary (Table 70).

Table 70 : ISS : Organ involvement for serious infections excluding
tuberculosis and

**Opportunistic infections -- (Data Available through August 31, 2001)**

> ![](media/image36.png){width="5.0in" height="5.041666666666667in"}

Table 71 presents the different kinds of serious infections observed
during the adequate and well-controlled studies.

Table 71 : ISS : Patients with serious infections -- adequate and
well-controlled studies

> ![](media/image37.png){width="4.625in" height="3.4895833333333335in"}
>
> ![](media/image38.png){width="4.583333333333333in"
> height="3.5833333333333335in"}

Infections that were associated with sepsis during the clinical
development program are listed in Table 72. Skin, musculoskeletal and
urinary infections were among those infections most frequently
associated with sepsis.

Table 72 : ISS : Infections Associated with Sepsis During the Adalimumab
Clinical Development Program

> ![](media/image39.png){width="4.989583333333333in"
> height="1.7708333333333333in"}

Table 73 summarizes all patients who experienced serious infections,
including the 4-month interim and final safety up-dates.

Table 73 : ISS : Overview of Serious Infections of Clinical Interest As
Reported in the ISS, Interim 4-Month Safety Update, and Final Safety
Update

+-----------------+------------+------------+------------+------------+
| Patients with   | Safety     |            |            | Total      |
| Any             | Data and   |            |            |            |
|                 | Up-Dates   |            |            |            |
+-----------------+------------+------------+------------+------------+
|                 | ISS        | 4-Month    | Final      |            |
|                 |            | Interim    |            |            |
|                 | BLA        |            | Up-Date    |            |
|                 | Submission | Up-Date    | ^3^        |            |
|                 | ^1^        | ^2^        |            |            |
+-----------------+------------+------------+------------+------------+
| SAE             | 575        | 241        | 160        | 976        |
+-----------------+------------+------------+------------+------------+
| Serious         | 129        | 35         | 38         | 202        |
| infection       |            |            |            |            |
+-----------------+------------+------------+------------+------------+
| Tuberculosis    | 9          | 1          | 3          | 13         |
+-----------------+------------+------------+------------+------------+
| Opportunistic   | 2          | 1          | 3          | 6          |
| Infection       |            |            |            |            |
+-----------------+------------+------------+------------+------------+

^1^ The ISS reported safety data through 31-Aug-2001 included in the
original submission

^2^ The 4-month safety update data from 31-Aug-2001 through
29-March-2002 and data that had not been reported in the original
submission

^3^ This safety update reported data from 29-March-2002 through
31-Aug-2002

A total of 202 adalimumab-treated patients (includes the final safety
up-date of 31-Aug-2002) experienced serious infections during the
clinical development program. Review of information provided on 186
subjects with serious infections, revealed a wide assortment of serious
infections. Based on this larger safety database, the order of frequency
remains similar; the serious infections observed were pulmonary,
musculoskeletal (including post-surgical), skin, gastrointestinal, and
genitourinary.

Representative serious pulmonary infections included various pneumonias,
some with empyema; musculoskeletal infections included septic arthritis,
post-surgical infections, and infected prostheses; infections of the
skin included erysipelas, cellulitis, and disseminated herpes zoster;
gastrointestinal infections included diverticulitis, appendicitis, and
diarrhea; genitourinary infections included pyelonephritis, and chronic
pyelonephritis.

Table 74 compares the serious infection incidence rates among RA
patients within the adalimumab clinical development program and
comparable population bases from published studies. There is
considerable variation in the reported rates for SAEs per 100 patient
years, varying from 3.1 to 9.5 events per 100 patient years. The
incidence rate for adalimumab-treated patients at the proposed dosage of
40 mg biweekly is at the lower end of that range, but is higher than the
rate for placebo-treated patients.

Table 74 : ISS : Comparable Serious Infection Incidence Rates Among RA
Patients

+-----------------------+-----------------+--------------+-------------+
| Study/Publication     | Population Base | Events/      |             |
|                       |                 |              |             |
|                       |                 | 100          |             |
|                       |                 | patient-yrs  |             |
+-----------------------+-----------------+--------------+-------------+
| Doran (2000) [^8]     | Mayo Clinic     | 3.1-9.5      |             |
+-----------------------+-----------------+--------------+-------------+
| Singh (1999) [^9]     | ARAMIS database |              |             |
+-----------------------+-----------------+--------------+-------------+
| Adalimumab clinical   |                 | 4.9          |             |
| development program   |                 |              |             |
+-----------------------+-----------------+--------------+-------------+
| Adalimumab 40 mg q2w  |                 | 3.9          |             |
| treatment group       |                 |              |             |
+-----------------------+-----------------+--------------+-------------+
| Adalimumab Trials     |                 | Adalimumab   | Placebo     |
| (AWC)                 |                 |              |             |
+-----------------------+-----------------+--------------+-------------+
|                       |                 | 4.8          | 1.9         |
+-----------------------+-----------------+--------------+-------------+

For both adalimumab- and placebo-treated patients, the rate of serious
infections was lower among patients \<65 years of age than for older
patients. (See Table 95 and Table 96.) Both of the patients who died of
serious infections were \>65 years of age (70 and 75 years), and both
patients with herpes zoster infections were \>65 years of age (66 and
70 years). Of note, both patients with fatal infections and both
patients with herpes zoster infections were among the patients taking
concomitant MTX.

> H. Tuberculosis and Other Opportunistic Infections

Nine cases of tuberculosis were observed during the clinical development
program (Table 76), five of which occurred among patients over age 65.
An additional four cases were provided with the Safety Update of August
31, 2002, yielding a total of thirteen cases. Infections included
miliary, lymphatic, peritoneal, and pulmonary tuberculosis. Most of the
cases of tuberculosis occurred within the first few months after
initiation of therapy and may reflect recrudescence of latent disease.

Occurrence of seven cases of tuberculosis out of 542 patients treated
(1.7%) early in the clinical trials prompted discussions between the
Agency and the sponsor and consideration of placing the clinical program
on hold. Thorough analysis of those 7 cases determined that ¾ of the
cases had baseline chest x-rays consistent with tuberculosis, suggesting
that screening might be an effective way to identify patients at risk.
At the recommendation of the FDA, the sponsor instituted measures for
screening and prophylaxis for all patients prior to enrollment. The
sponsor adopted screening procedures consisting of chest x-ray in Europe
and PPD plus chest x-ray in the U.S. and initiation of appropriate
prophylactic tuberculosis treatment in accordance with the CDC
Guidelines (Table 75).

The incidence of cases of reactivation tuberculosis promptly decreased
after initiation of this program, and the proposed labeling supports
these recommendations.

Six cases of invasive opportunistic infections caused by histoplasma,
aspergillus, and nocardia were also reported in clinical trials.

Table 75 : ISS : Screening prophylaxis methodology employed and maximum
dose administered during the adalimumab clinical development program

> ![](media/image40.png){width="5.09375in" height="2.15625in"}

Continued monitoring of adalimumab-treated patients for additional
examples of serious and opportunistic infections is needed.

Table 76 : ISS : Listing of tuberculosis cases observed in the
adalimumab clinical development program

<table>
<colgroup>
<col style="width: 16%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 11%" />
<col style="width: 12%" />
<col style="width: 30%" />
</colgroup>
<tbody>
<tr class="odd">
<td><h1 id="study-grouping">Study grouping</h1></td>
<td><p><strong>Initial</strong></p>
<p><strong>Study</strong></p></td>
<td><p><strong>Patient</strong></p>
<p><strong>number</strong></p></td>
<td><strong>Sex</strong></td>
<td><strong>Country</strong></td>
<td><p><strong>Age</strong></p>
<p><strong>(yrs)</strong></p></td>
<td><p><strong>Day on</strong></p>
<p><strong>drug at</strong></p>
<p><strong>onset</strong></p></td>
<td><p><strong>Dose and</strong></p>
<p><strong>schedule at onset</strong></p></td>
<td><p><strong>Protocol requires</strong></p>
<p><strong>screening<sup>a</sup>/</strong></p>
<p><strong>exclusion</strong></p></td>
<td><h4 id="comments">Comments</h4></td>
</tr>
<tr class="even">
<td rowspan="8"><p><strong>Open-label</strong></p>
<p>continuation studies</p></td>
<td>DE001</td>
<td>114</td>
<td>F</td>
<td>Germany</td>
<td>67</td>
<td>100</td>
<td>10 mg/kg q4wk iv</td>
<td><p>No/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered.</td>
</tr>
<tr class="odd">
<td>DE004</td>
<td>16</td>
<td>F</td>
<td>Germany</td>
<td>71</td>
<td>116</td>
<td>1 mg/kg wk sc</td>
<td><p>No/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered.</td>
</tr>
<tr class="even">
<td>DE001</td>
<td>111</td>
<td>F</td>
<td>Germany</td>
<td>67</td>
<td>202</td>
<td>5 mg/kg q4wk iv</td>
<td><p>No/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered.</td>
</tr>
<tr class="odd">
<td>DE010</td>
<td>305</td>
<td>M</td>
<td>Germany</td>
<td>63</td>
<td>183</td>
<td>1 mg/kg eow sc</td>
<td><p>No/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered.</td>
</tr>
<tr class="even">
<td>DE011</td>
<td>3511</td>
<td>F</td>
<td>Germany</td>
<td>67</td>
<td>351</td>
<td>40 mg eow sc</td>
<td><p>Yes/Yes</p>
<p>PPD-not done</p>
<p>Chest X-ray neg</p></td>
<td>Recovered. Case entered into database after clinical cut-off of 31-
Aug-01.</td>
</tr>
<tr class="odd">
<td>DE001</td>
<td>106</td>
<td>F</td>
<td>Germany</td>
<td>45</td>
<td>431</td>
<td>3 mg/kg q4wk iv</td>
<td><p>No/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered.</td>
</tr>
<tr class="even">
<td>DE007</td>
<td>2110</td>
<td>F</td>
<td>UK</td>
<td>68</td>
<td>219</td>
<td>40 mg wk sc</td>
<td><p>Yes/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered.</td>
</tr>
<tr class="odd">
<td>DE007</td>
<td>2506</td>
<td>F</td>
<td>Spain</td>
<td>57</td>
<td>241</td>
<td>80 mg wk sc</td>
<td><p>Yes/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered.</td>
</tr>
<tr class="even">
<td><p><strong>Adequate and well-</strong></p>
<p><strong>controlled studies</strong></p></td>
<td>DE019</td>
<td>3813</td>
<td>F</td>
<td>US</td>
<td>28</td>
<td>106</td>
<td>40 mg eow sc</td>
<td><p>Yes/No<sup>b</sup></p>
<p>PPD- neg</p>
<p>Chest X-ray neg</p></td>
<td>Not resolved. Primary case. Patient had recent family exposure to
tuberculosis.</td>
</tr>
<tr class="odd">
<td rowspan="3"><p><strong>Long-term post-</strong></p>
<p><strong>study follow-up</strong></p></td>
<td>DE011</td>
<td>4801</td>
<td>M</td>
<td>Italy</td>
<td>45</td>
<td>--</td>
<td>Post-study</td>
<td><p>Yes/Yes</p>
<p>PPD-not done</p>
<p>Chest X-ray neg</p></td>
<td>Off adalimumab for 4 months.</td>
</tr>
<tr class="even">
<td>DE011</td>
<td>3408</td>
<td>F</td>
<td>Germany</td>
<td>28</td>
<td>--</td>
<td>Placebo</td>
<td><p>Yes/Yes</p>
<p>PPD-not done</p>
<p>Chest X-ray neg</p></td>
<td>Placebo-treated patient (ie, did not receive adalimumab).</td>
</tr>
<tr class="odd">
<td>DE007</td>
<td>1507</td>
<td>F</td>
<td>Germany</td>
<td>70</td>
<td>184</td>
<td>Post-study</td>
<td><p>Yes/No</p>
<p>No screening done <sup>c</sup></p></td>
<td>Recovered. Seventy (70) days post adalimumab treatment. Prior
treatment was 40 mg weekly.</td>
</tr>
<tr class="even">
<td colspan="10"><blockquote>
<p>F = female M = male wk = weekly eow = every other week q4wk = every 4
weeks sc = subcutaneous iv = intravenous</p>
<p><sup>a</sup> Screening by chest x-ray in EU/Australia and PPD skin
test in US/Canada</p>
<p><sup>b</sup> Prophylaxis recommended but not mandatory</p>
<p><sup>c</sup> For the eight patients that had no screening tests
performed, retrospective review of previous chest x-rays by two
radiologists revealed that 6 of the 8 patients had some finding
consistent with possible old tuberculosis infection</p>
</blockquote></td>
</tr>
</tbody>
</table>

> I. ANA and Anti-dsDNA

In the controlled trials, increases in ANA and anti-dsDNA titers were
observed more frequently in adalimumab-treated patients than in
placebo-treated patients. At Week 24, 12% of adalimumab-treated patients
and 7% of placebo-treated patients shifted from ANA negative at baseline
to positive (Table 77).

Table 77 : ISS : ANA Shift -- Baseline To LOCF Weeks 12 and 24 ^a^ --

**Adequate and well-Controlled Studies by randomized treatment (safety
set)**

<table>
<colgroup>
<col style="width: 24%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td><p>20 mg</p>
<p>q2w</p></td>
<td colspan="3"><p>20 mg</p>
<p>qw</p></td>
<td colspan="2"><p>40 mg</p>
<p>q2w</p></td>
<td>40 mg qw</td>
<td><p>80 mg</p>
<p>q2w</p></td>
<td colspan="2"><p>All</p>
<p>adalimumab</p>
<p>N = 1289</p></td>
<td colspan="2">Placebo N =640</td>
</tr>
<tr class="even">
<td></td>
<td colspan="12"><strong>Baseline negative patients</strong></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td><strong>%</strong> <sup>1</sup></td>
<td></td>
<td></td>
<td></td>
<td><strong>%</strong> <sup>1</sup></td>
<td></td>
<td><strong>%</strong> <sup>1</sup></td>
</tr>
<tr class="even">
<td>Baseline negative/ negative at Week 12</td>
<td colspan="2">124</td>
<td>221</td>
<td colspan="2">475</td>
<td><strong>86</strong></td>
<td>72</td>
<td>42</td>
<td>934</td>
<td><strong>88</strong></td>
<td>484</td>
<td><strong>90</strong></td>
</tr>
<tr class="odd">
<td>Baseline negative/ negative at Week 24 <sup>b</sup></td>
<td colspan="2">127</td>
<td>213</td>
<td colspan="2">455</td>
<td><strong>82</strong></td>
<td>76</td>
<td>43</td>
<td>914</td>
<td><strong>86</strong></td>
<td>493</td>
<td><strong>92</strong></td>
</tr>
<tr class="even">
<td>Baseline negative/ positive at Week 12</td>
<td colspan="2">13</td>
<td>25</td>
<td colspan="2">51</td>
<td><strong>9</strong></td>
<td>15</td>
<td>0</td>
<td>104</td>
<td><strong>10</strong></td>
<td>42</td>
<td><strong>8</strong></td>
</tr>
<tr class="odd">
<td>Baseline negative/ positive at Week 24 <sup>b</sup></td>
<td colspan="2">11</td>
<td>33</td>
<td colspan="2">77</td>
<td><strong>14</strong></td>
<td>11</td>
<td>0</td>
<td>132</td>
<td><strong>12</strong></td>
<td>39</td>
<td><strong>7</strong></td>
</tr>
</tbody>
</table>

^1^ Percentage of maximal number of observations among patients with
negative ANA at baseline

^a^ Data from Study De031 reports maximum ANA at Weeks 12 and 24 instead
of LOCF Week 12 and 24; baseline positive to Week 12 or 24 positive
determined by subtraction.

^b^ Data from Study De011 substitutes Week 26 for Week 24.

> J. Lupus-Like Syndromes

A few cases of lupus-like syndromes with skin rash, serositis, and
positive serologies were seen (Table 78). One patient treated with
adalimumab developed clinical signs suggestive of new-onset lupus-like
syndrome. The patient improved following discontinuation of therapy.

A worldwide search of the safety database (reported November 26, 2002)
revealed 4 cases of pleural effusion, 3 cases of pericarditis, and 1
case of pericarditis and pleuritis among adalimumab-treated patients.
Information on these cases is still sketchy. Therefore, the role of
adalimumab usage in the occurrence of these cases is currently unclear.
One case of pleuritis was attributed to be manifestations of the
underlying rheumatoid arthritis by biopsy, and one case of pleural
effusion was later attributed to tuberculosis. Several of these cases
were evaluated for drug-induced lupus erythematosus, but no evidence was
found.

The impact of long-term treatment with adalimumab on the development of
autoimmune diseases is unknown

Table 78 : ISS : Listing of the lupus-like cases observed during the
adalimumab clinical development program

+---------+-----+---+---+-----+----------+-------------------------+
| **      | **  | * | * | **  | **Dose   | **Comments**            |
| Initial | Pat | * | * | Day | and**    |                         |
| study** | ien | S | A | o   |          |                         |
|         | t** | e | g | n** | **       |                         |
|         |     | x | e |     | schedule |                         |
|         | *   | * | * | **d | at**     |                         |
|         | *nu | * | * | rug |          |                         |
|         | mbe |   |   | a   | *        |                         |
|         | r** |   | * | t** | *onset** |                         |
|         |     |   | * |     |          |                         |
|         |     |   | ( | **o |          |                         |
|         |     |   | y | nse |          |                         |
|         |     |   | r | t** |          |                         |
|         |     |   | s |     |          |                         |
|         |     |   | ) |     |          |                         |
|         |     |   | * |     |          |                         |
|         |     |   | * |     |          |                         |
+---------+-----+---+---+-----+----------+-------------------------+
| DE001   | 94  | F | 4 | 1   | 40 mg    | Skin rash and positive  |
|         |     |   | 8 | 428 | q2w sc   | serologies              |
+---------+-----+---+---+-----+----------+-------------------------+
| DE007   | 1   | F | 7 | 168 | 40 mg wk | Serositis and positive  |
|         | 526 |   | 0 |     | sc       | serologies              |
+---------+-----+---+---+-----+----------+-------------------------+
| DE010   | 103 | F | 4 | 418 | 1 mg/kg  | Undocumented serositis  |
|         |     |   | 9 |     | q2w sc   | and positive serologies |
+---------+-----+---+---+-----+----------+-------------------------+
| DE011   | 113 | F | 4 | 107 | 20 mg wk | Probable lupus before   |
|         |     |   | 5 |     | sc       | study,                  |
|         |     |   |   |     |          |                         |
|         |     |   |   |     |          | exacerbation with       |
|         |     |   |   |     |          | neutropenia and         |
|         |     |   |   |     |          | elevated serologies     |
+---------+-----+---+---+-----+----------+-------------------------+
| F =     |     |   |   |     |          |                         |
| female  |     |   |   |     |          |                         |
| wk =    |     |   |   |     |          |                         |
| weekly  |     |   |   |     |          |                         |
| q2w =   |     |   |   |     |          |                         |
| every   |     |   |   |     |          |                         |
| other   |     |   |   |     |          |                         |
| week sc |     |   |   |     |          |                         |
| =       |     |   |   |     |          |                         |
| subcu   |     |   |   |     |          |                         |
| taneous |     |   |   |     |          |                         |
+---------+-----+---+---+-----+----------+-------------------------+

> K. Immunologic Reactions

Table 79 lists the immunologic reactions observed during the clinical
development program. They were primarily allergic rashes (14), infusion
reactions (7), urticarial reactions (6), and anaphylactic reactions (4).

L. Demyelinating Disease

Table 80 lists the three cases of possible demyelinating disease
observed during the clinical development program of adalimumab.
Demyelinating disease has been observed in studies of many TNF blockers,
including etanercept, infliximab, and lenercept.[^10] Of note, one
normal volunteer developed demyelinating disease after a single dose of
adalimumab. Two of the 3 patients had complete recovery, the other has
residual leg numbness.

.

> M. AEs Leading to Withdrawal, Interruption, and Reduction of Study
> Drug

The most frequent reasons for withdrawal were adverse events, lack of
efficacy, and withdrawal of consent. At the recommended dose (40 mg
biweekly), AEs among adalimumab-treated patients leading to temporary
withdrawal occurred in 18% and permanent withdrawal in 6% of
adalimumab-treated patients. The most common adverse events leading to
discontinuation of adalimumab were clinical flare reaction (0.7%), rash
(0.3%) and pneumonia (0.3%). The incidence of temporary withdrawal was
higher with weekly dosing and intravenous administration (Table 81).

Table 79 : ISS :Listing of the immunologic reactions observed during the
adalimumab clinical development program

+------------+-----+----+---+---+---+--------+------+-----------------+
| # Type     | **I | *  | * | * | * | **Dose | **S  | **Comments**    |
|            | nit | *P | * | * | * | and**  | AE** |                 |
|            | ial | at | S | A | D |        |      |                 |
|            | s   | ie | e | g | a | **sc   | **   |                 |
|            | tud | nt | x | e | y | hedule | Yes/ |                 |
|            | y** | ** | * | * | o | at     | No** |                 |
|            |     |    | * | * | n | o      |      |                 |
|            |     | ** |   |   | * | nset** |      |                 |
|            |     | nu |   | * | * |        |      |                 |
|            |     | mb |   | * |   |        |      |                 |
|            |     | er |   | ( | * |        |      |                 |
|            |     | ** |   | y | * |        |      |                 |
|            |     |    |   | r | d |        |      |                 |
|            |     |    |   | s | r |        |      |                 |
|            |     |    |   | ) | u |        |      |                 |
|            |     |    |   | * | g |        |      |                 |
|            |     |    |   | * | a |        |      |                 |
|            |     |    |   |   | t |        |      |                 |
|            |     |    |   |   | * |        |      |                 |
|            |     |    |   |   | * |        |      |                 |
|            |     |    |   |   |   |        |      |                 |
|            |     |    |   |   | * |        |      |                 |
|            |     |    |   |   | * |        |      |                 |
|            |     |    |   |   | o |        |      |                 |
|            |     |    |   |   | n |        |      |                 |
|            |     |    |   |   | s |        |      |                 |
|            |     |    |   |   | e |        |      |                 |
|            |     |    |   |   | t |        |      |                 |
|            |     |    |   |   | * |        |      |                 |
|            |     |    |   |   | * |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
| #######    | DE  | 28 | F | 4 | 2 | 1      | Yes  | Repeat          |
| ## Infusio | 001 |    |   | 8 | 7 | mg/kg  |      | administration  |
| n reaction |     |    |   |   |   | Q4wk   |      | at slower rate. |
|            |     |    |   |   |   | iv     |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 43 | F | 6 | 2 | 1      | No   | Repeat          |
|            | 001 |    |   | 3 | 7 | mg/kg  |      | administration  |
|            |     |    |   |   |   | Q4wk   |      | at slower rate. |
|            |     |    |   |   |   | iv     |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 21 | F | 2 | 4 | 1      | Yes  | Discontinued    |
|            | 001 |    |   | 6 | 3 | mg/kg  |      | from study.     |
|            |     |    |   |   |   | Q4wk   |      |                 |
|            |     |    |   |   |   | iv     |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 5  | F | 2 | 2 | 3      | Yes  | Vasovagal       |
|            | 001 | 3^ |   | 4 | 9 | mg/kg  |      | event.          |
|            |     | a^ |   |   | 6 | eow iv |      | Discontinued    |
|            |     |    |   |   |   |        |      | from study.     |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 82 | F | 7 | 8 | 3      | No   | No comments.    |
|            | 001 |    |   | 6 | 5 | mg/kg  |      |                 |
|            |     |    |   |   | 7 | eow iv |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 85 | F | 4 | 1 | 3      | No   | Two episodes.   |
|            | 001 |    |   | 7 | 4 | mg/kg  |      | Discontinued    |
|            |     |    |   |   | 3 | eow iv |      | from study.     |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 1  | F | 4 | 2 | 3      | Yes  | No comments.    |
|            | 001 | 23 |   | 5 | 6 | mg/kg  |      |                 |
|            |     |    |   |   | 5 | Q4wk   |      |                 |
|            |     |    |   |   |   | iv     |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            |     |    |   |   |   |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
| **Ana      | DE  | 22 | F | 3 | 4 | 40 mg  | No   | No comments.    |
| phylactoid | 007 | 01 |   | 6 | 0 | wk sc  |      |                 |
| reaction** |     |    |   |   | 7 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 24 | M | 5 | 3 | 80 mg  | No   | No comments.    |
|            | 007 | 15 |   | 3 | 1 | wk sc  |      |                 |
|            |     |    |   |   | 5 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 24 | F | 5 | 2 | 20 mg  | No   | Flu-symptoms,   |
|            | 007 | 23 |   | 1 | 1 | wk sc  |      | three episodes. |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 99 | F | 3 | 2 | 20 mg  | No   | No comments.    |
|            | 019 | 03 |   | 9 | 2 | wk sc  |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            |     |    |   |   |   |        |      | No comments.    |
+------------+-----+----+---+---+---+--------+------+-----------------+
| **Other    | DE  | 15 | F | 7 | 1 | 40 mg  | Yes  | Lupus-like      |
| systemic   | 007 | 26 |   | 0 | 6 | wk sc  |      | illness.        |
| reaction** |     |    |   |   | 8 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 48 | M | 6 | 1 | 40 mg  | Yes  | Imm             |
|            | 019 | 14 |   | 5 | 1 | eow sc |      | unosuppression. |
|            |     |    |   |   | 8 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            |     |    |   |   |   |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
| **Allergic | DE  | 95 | F | 4 | 1 | 5      | No   | No comments.    |
| rash**     | 001 |    |   | 0 | 4 | mg/kg  |      |                 |
|            |     |    |   |   |   | q4w iv |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 4  | F | 6 | 5 | 40 mg  | No   | No comments.    |
|            | 007 | 14 |   | 4 | 1 | wk sc  |      |                 |
|            |     |    |   |   | 8 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 16 | M | 6 | 8 | 80 mg  | No   | No comments.    |
|            | 007 | 10 |   | 7 | 4 | wk sc  |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 17 | F | 5 | 7 | 80 mg  | No   | No comments.    |
|            | 007 | 01 |   | 8 | 9 | wk sc  |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 22 | F | 6 | 7 | 40 mg  | No   | No comments.    |
|            | 007 | 05 |   | 7 | 9 | eow sc |      |                 |
|            |     |    |   |   | 7 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 22 | F | 4 | 9 | 40 mg  | No   | No comments.    |
|            | 007 | 08 |   | 6 | 5 | eow sc |      |                 |
|            |     |    |   |   | 7 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 23 | F | 7 | 9 | 40 mg  | No   | No comments.    |
|            | 007 | 25 |   | 1 | 6 | eow sc |      |                 |
|            |     |    |   |   | 2 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 1  | F | 6 | 1 | 40 mg  | No   | No comments.    |
|            | 010 | 09 |   | 7 | 3 | eow sc |      |                 |
|            |     |    |   |   | 2 |        |      |                 |
|            |     |    |   |   | 2 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 14 | F | 3 | 1 | 40 mg  | No   | Two episodes.   |
|            | 011 | 04 |   | 6 | 0 | eow sc |      |                 |
|            |     |    |   |   | 1 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+
|            | DE  | 30 | F | 5 | 1 | 20 mg  | No   | No comments.    |
|            | 011 | 20 |   | 0 | 0 | wk sc  |      |                 |
|            |     |    |   |   | 3 |        |      |                 |
+------------+-----+----+---+---+---+--------+------+-----------------+

<table>
<colgroup>
<col style="width: 19%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 15%" />
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 15%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Type</strong></td>
<td><strong>Initial study</strong></td>
<td><p><strong>Patient</strong></p>
<p><strong>number</strong></p></td>
<td><strong>Sex</strong></td>
<td><p><strong>Age</strong></p>
<p><strong>(yrs)</strong></p></td>
<td><p><strong>Day on</strong></p>
<p><strong>drug at</strong></p>
<p><strong>onset</strong></p></td>
<td><p><strong>Dose and</strong></p>
<p><strong>schedule at onset</strong></p></td>
<td><p><strong>SAE</strong></p>
<p><strong>Yes/No</strong></p></td>
<td></td>
<td><strong>Comments</strong></td>
</tr>
<tr class="even">
<td></td>
<td>DE011</td>
<td>3809</td>
<td>F</td>
<td>37</td>
<td>10</td>
<td>20 mg eow sc</td>
<td>No</td>
<td colspan="2"><p>Two episodes,</p>
<p>232 days apart.</p></td>
</tr>
<tr class="odd">
<td></td>
<td>DE011</td>
<td>3816</td>
<td>F</td>
<td>54</td>
<td>11</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>DE011</td>
<td>4401</td>
<td>F</td>
<td>70</td>
<td>314</td>
<td>40 mg wk sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>DE011</td>
<td>5031</td>
<td>F</td>
<td>58</td>
<td>14</td>
<td>40 mg wk sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Urticaria-type reactions</strong></td>
<td>DE007</td>
<td>2101</td>
<td>F</td>
<td>62</td>
<td>733</td>
<td>40 mg q6w sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>DE019</td>
<td>5904</td>
<td>F</td>
<td>50</td>
<td>14</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>Two episodes.</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>DE019</td>
<td>9305</td>
<td>F</td>
<td>43</td>
<td>20</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>DE019</td>
<td>9604</td>
<td>F</td>
<td>49</td>
<td>56</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>DE031</td>
<td>11908</td>
<td>F</td>
<td>61</td>
<td>265</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>Two episodes.</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>DE031</td>
<td>12810</td>
<td>F</td>
<td>68</td>
<td>57</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>Fixed drug eruption</strong></td>
<td>DE001</td>
<td>53<sup>a</sup></td>
<td>F</td>
<td>24</td>
<td>28</td>
<td>3 mg/kg q4w iv</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>DE031</td>
<td>9003</td>
<td>F</td>
<td>24</td>
<td>86</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Lupus-skin reaction</strong></td>
<td>DE010</td>
<td>103</td>
<td>F</td>
<td>49</td>
<td>418</td>
<td>1 mg/kg eow sc</td>
<td>Yes</td>
<td colspan="2">No systemic symptoms.</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Allergic reaction</strong></td>
<td>DE001</td>
<td>7</td>
<td>F</td>
<td>27</td>
<td>41</td>
<td>1 mg/kg q4w iv</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="even">
<td><strong>unspecified</strong></td>
<td>DE007</td>
<td>2507</td>
<td>M</td>
<td>53</td>
<td>880</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>DE009</td>
<td>802</td>
<td>F</td>
<td>60</td>
<td>340</td>
<td>40 mg eow sc</td>
<td>No</td>
<td>No comments.</td>
<td></td>
</tr>
<tr class="even">
<td colspan="10"><p>F = female M = male</p>
<p>wk = weekly</p>
<p>eow = every other week</p>
<p>qxwk = every x weeks</p>
<p>sc = subcutaneous</p>
<p>iv = intravenous</p>
<p><sup>a</sup> This patient had two different and separate allergic
type reactions</p></td>
</tr>
</tbody>
</table>

Table 80 : ISS : Listing of cases of possible demyelinating disease
observed in the adalimumab clinical

# development program 

+------+---+---+---+---+-----+---------------+-------------------------+
| **I  | * | * | * | * | **D | **Comments**  | **Post Study            |
| niti | * | * | * | * | ose |               | Follow-up**             |
| al** | P | S | A | D | an  |               |                         |
|      | a | e | g | a | d** |               |                         |
| *    | t | x | e | y |     |               |                         |
| *stu | i | * | * | o | *   |               |                         |
| dy** | e | * | * | n | *sc |               |                         |
|      | n |   |   | * | hed |               |                         |
|      | t |   | * | * | ule |               |                         |
|      | * |   | * |   | at  |               |                         |
|      | * |   | ( | * | o   |               |                         |
|      |   |   | y | * | nse |               |                         |
|      | * |   | r | d | t** |               |                         |
|      | * |   | s | r |     |               |                         |
|      | n |   | ) | u |     |               |                         |
|      | u |   | * | g |     |               |                         |
|      | m |   | * | a |     |               |                         |
|      | b |   |   | t |     |               |                         |
|      | e |   |   | * |     |               |                         |
|      | r |   |   | * |     |               |                         |
|      | * |   |   |   |     |               |                         |
|      | * |   |   | * |     |               |                         |
|      |   |   |   | * |     |               |                         |
|      |   |   |   | o |     |               |                         |
|      |   |   |   | n |     |               |                         |
|      |   |   |   | s |     |               |                         |
|      |   |   |   | e |     |               |                         |
|      |   |   |   | t |     |               |                         |
|      |   |   |   | * |     |               |                         |
|      |   |   |   | * |     |               |                         |
+------+---+---+---+---+-----+---------------+-------------------------+
| # D  | 2 | F | 5 | 2 | 40  | Optic         | Patient treated acutely |
| E009 | 5 |   | 0 | 4 | mg  | neuritis and  | for optic neuritis with |
|      | 0 |   |   | 3 | eow | subsequent    | high dose               |
|      | 8 |   |   |   | sc  | positive MRI. | corticosteroids,        |
|      |   |   |   |   |     |               | improved and continued  |
|      |   |   |   |   |     |               | on adalimumab. MRI      |
|      |   |   |   |   |     |               | consistent with         |
|      |   |   |   |   |     |               | demyelinating disease.  |
|      |   |   |   |   |     |               | The patient remains     |
|      |   |   |   |   |     |               | asymptomatic and has    |
|      |   |   |   |   |     |               | stopped taking          |
|      |   |   |   |   |     |               | adalimumab              |
+------+---+---+---+---+-----+---------------+-------------------------+
| **   | 7 | M | 3 | 8 | 1   | Paresthesias  | Patient had mild to     |
| DE02 | 7 |   | 0 |   | mg  | in healthy    | moderate paresthesias   |
| 4C** |   |   |   |   | /kg | volunteer.    | of the upper and lower  |
|      |   |   |   |   | iv  |               | extremities. MRI        |
|      |   |   |   |   |     |               | consistent with old     |
|      |   |   |   |   |     |               | demyelinating disease   |
|      |   |   |   |   |     |               | (no lesions enhanced    |
|      |   |   |   |   |     |               | with contrast           |
|      |   |   |   |   |     |               | material). Treated with |
|      |   |   |   |   |     |               | high dose               |
|      |   |   |   |   |     |               | corticosteroids and has |
|      |   |   |   |   |     |               | recovered off any       |
|      |   |   |   |   |     |               | medications.            |
+------+---+---+---+---+-----+---------------+-------------------------+
| *    | 9 | F | 5 | 2 | 20  | Paresthesias  | Patient had episodes of |
| *DE0 | 7 |   | 2 | 8 | mg  | treated with  | lower extremity         |
| 19** | 1 |   |   |   | wk  | Copaxone.     | numbness. MRI           |
|      | 0 |   |   |   | sc  |               | consistent with         |
|      |   |   |   |   |     |               | demyelinating disease.  |
|      |   |   |   |   |     |               | Treated with glatiramer |
|      |   |   |   |   |     |               | acetate and improved.   |
|      |   |   |   |   |     |               | Jan-02 the glatirarner  |
|      |   |   |   |   |     |               | acetate was             |
|      |   |   |   |   |     |               | discontinued secondary  |
|      |   |   |   |   |     |               | to headaches and the    |
|      |   |   |   |   |     |               | patient was placed on   |
|      |   |   |   |   |     |               | interferon beta-1b. The |
|      |   |   |   |   |     |               | interferon beta-1b was  |
|      |   |   |   |   |     |               | discontinued in May-02. |
|      |   |   |   |   |     |               | At this time the        |
|      |   |   |   |   |     |               | patient has             |
|      |   |   |   |   |     |               | intermittent right leg  |
|      |   |   |   |   |     |               | numbness and is able to |
|      |   |   |   |   |     |               | perform all activities  |
|      |   |   |   |   |     |               | of daily living.        |
+------+---+---+---+---+-----+---------------+-------------------------+
| F =  |   |   |   |   |     |               |                         |
| fe   |   |   |   |   |     |               |                         |
| male |   |   |   |   |     |               |                         |
| M =  |   |   |   |   |     |               |                         |
| male |   |   |   |   |     |               |                         |
| wk = |   |   |   |   |     |               |                         |
| we   |   |   |   |   |     |               |                         |
| ekly |   |   |   |   |     |               |                         |
| eow  |   |   |   |   |     |               |                         |
| =    |   |   |   |   |     |               |                         |
| e    |   |   |   |   |     |               |                         |
| very |   |   |   |   |     |               |                         |
| o    |   |   |   |   |     |               |                         |
| ther |   |   |   |   |     |               |                         |
| week |   |   |   |   |     |               |                         |
|      |   |   |   |   |     |               |                         |
| sc = |   |   |   |   |     |               |                         |
| subc |   |   |   |   |     |               |                         |
| utan |   |   |   |   |     |               |                         |
| eous |   |   |   |   |     |               |                         |
| iv = |   |   |   |   |     |               |                         |
| int  |   |   |   |   |     |               |                         |
| rave |   |   |   |   |     |               |                         |
| nous |   |   |   |   |     |               |                         |
+------+---+---+---+---+-----+---------------+-------------------------+

Table 81 : ISS : Adverse Events Leading to Withdrawal, Temporary
Interruption , and Reduction of Study Drug

  -------------- ---------------- ------- ----------- ------- ------------ --------- ----------- ------- ------------ ------- ----------- ------- -------------- -------
                 **Adalimumab**                                                                                                                                  

                 **20 mg sc q2w**         **20 mg sc          **40 mg sc             **40 mg sc          **All sc**           **All IV**          **All          
                                          qw**                q2w**                  qw**                                                         Adalimumab**   

                 **N= 175**               **N=397**           **N=1903**             **N=466**           **N=2263**           **N=197**           **N=2334**     

  **Any adverse  **N**            **%**   **N**       **%**   **N**        **%**     **N**       **%**   **N**        **%**   **N**       **%**   **N**          **%**
  event**                                                                                                                                                        

  **AEs leading  11               6       29          7       **114**      **6**     29          6       211          9       42          21      252            11
  to permanent                                                                                                                                                   
  withdrawal                                                                                                                                                     
  ^1^**                                                                                                                                                          

  **AEs leading  16               9       91          23      **340**      **18**    103         22      576          26      53          27      614            26
  to temporary                                                                                                                                                   
  interruption                                                                                                                                                   
  ^2^**                                                                                                                                                          

  **AEs leading  0                0       2           1       **2**        **\<1**   1           \<1     7            \<1     16          8       23             1
  to dose                                                                                                                                                        
  reduction                                                                                                                                                      
  ^3^**                                                                                                                                                          
  -------------- ---------------- ------- ----------- ------- ------------ --------- ----------- ------- ------------ ------- ----------- ------- -------------- -------

Reviewer's Table

1 Source of data: sponsor's Table 5.3.11

2 Source of data: sponsor's Table 5.3.12

3 Source of data: sponsor's Table 5.3.13

N. Laboratory Abnormalities

> 1\. Hematologic Changes

Adalimumab-treated patients demonstrated elevations of red blood cells,
hemoglobin, and hematocrit levels and reductions in leucocytes,
primarily neutrophils (Table 82). To a great extent this represents
normalization of abnormal deviations associated with their chronic
disease.

Table 82 : ISS : Hematology Changes From Baseline in Adequate and
Well-Controlled Studies by Randomized Treatment

+---------------+----------------+----+------------+-------------------+
|               | **Adalim       |    |            | **Placebo-Treated |
|               | umab-Treated** |    |            | Patients**        |
|               |                |    |            |                   |
|               | **Patients**   |    |            |                   |
+---------------+----------------+----+------------+-------------------+
| **            | **Mean         | *  |            | **Mean change**   |
| Hematological | change**       | *C |            |                   |
| Parameter**   |                | om |            | **LOCF Week 24**  |
|               | **LOCF Week    | me |            |                   |
|               | 24**           | nt |            |                   |
|               |                | ** |            |                   |
+---------------+----------------+----+------------+-------------------+
| Hemoglobin    | **↑**4.2 g/L   | C  |            | **↑**0.7 g/L      |
|               | \*             | ha |            |                   |
|               |                | ng |            |                   |
|               |                | es |            |                   |
|               |                | g  |            |                   |
|               |                | re |            |                   |
|               |                | at |            |                   |
|               |                | er |            |                   |
|               |                | wi |            |                   |
|               |                | th |            |                   |
|               |                | hi |            |                   |
|               |                | gh |            |                   |
|               |                | er |            |                   |
|               |                | d  |            |                   |
|               |                | os |            |                   |
|               |                | es |            |                   |
+---------------+----------------+----+------------+-------------------+
| WBC           | **↓**0.6 x     | Ne |            | **↑**0.1 x        |
|               | 10^9^/L \*     | ut |            | 10^9^/L           |
|               |                | ap |            |                   |
|               |                | hi |            |                   |
|               |                | ls |            |                   |
|               |                | d  |            |                   |
|               |                | ec |            |                   |
|               |                | re |            |                   |
|               |                | as |            |                   |
|               |                | ed |            |                   |
|               |                | ;  |            |                   |
|               |                | l  |            |                   |
|               |                | ym |            |                   |
|               |                | ph |            |                   |
|               |                | oc |            |                   |
|               |                | yt |            |                   |
|               |                | es |            |                   |
|               |                | i  |            |                   |
|               |                | nc |            |                   |
|               |                | re |            |                   |
|               |                | as |            |                   |
|               |                | ed |            |                   |
+---------------+----------------+----+------------+-------------------+
|               | WBC**↓**0.8x   |    |            |                   |
|               | 10^9^/L \*     |    |            |                   |
|               |                |    |            |                   |
|               | Neutrophils    |    |            |                   |
|               | **↓**8%        |    |            |                   |
|               |                |    |            |                   |
|               | Lymphocytes    |    |            |                   |
|               | **↑** 7%       |    |            |                   |
+---------------+----------------+----+------------+-------------------+
| Basophils     | Mean changes   |    |            |                   |
|               | in percentages |    |            |                   |
|               |                |    |            |                   |
|               | were very      |    |            |                   |
|               | small          |    |            |                   |
+---------------+----------------+----+------------+-------------------+
| Eosinophils   |                |    |            |                   |
+---------------+----------------+----+------------+-------------------+
| Monocytes     |                |    |            |                   |
+---------------+----------------+----+------------+-------------------+
| Platelet      | **↓**33.2 x    |    | Changes    | **↑**3.3 x        |
| count         | **1**0^9^/L    |    | greater    | **1**0^9^/L       |
|               |                |    | with       |                   |
|               |                |    | higher     |                   |
|               |                |    | doses      |                   |
+---------------+----------------+----+------------+-------------------+
|               | **↓**33.5 x    |    |            |                   |
|               | **1**0^9^/L    |    |            |                   |
+---------------+----------------+----+------------+-------------------+
| Hematocrit    | Similar to     |    |            |                   |
|               | hemoglobin     |    |            |                   |
+---------------+----------------+----+------------+-------------------+
| RBC           |                |    |            |                   |
+---------------+----------------+----+------------+-------------------+

> \* p ≤ 0.001
>
> **2. Laboratory Changes**

Many subjects (5% to 13 %) had uric acid levels higher than the upper
limit of normal (ULN) at baseline. Hyperuricemia was only graded as 1
(\>ULN to ≤ 10 mg/DL) or 4 (≥10 mg/DL) with no grading in-between.
Adalimumab-treated patients demonstrated a higher frequency of Grade 4
hyperuricemia than placebo-treated patients during the clinical trials
(Table 83). However, nineteen of these twenty subjects demonstrated
elevation of uric acid at baseline (10 had Grade 1, and 9 had Grade 4).
One adalimumab-treated patient developed an episode of gout and another
an episode of nephrolithiasis.

Table 83 : ISS : CTC Grade 3 and 4 Laboratory Changes from Baseline
Recorded During Clinical Development Program

+---------------------------+------+------+------+------+------+------+
| ####### Study             | **   |      |      | **P  |      |      |
|  Group & Test Abnormality | Adal |      |      | lace |      |      |
|                           | imum |      |      | bo-T |      |      |
|                           | ab-T |      |      | reat |      |      |
|                           | reat |      |      | ed** |      |      |
|                           | ed** |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| **Clinical Pharmacology   | **G  | **G  | ###  | *    | ##   | **T  |
| HV**                      | rade | rade | # To | *Gra | ## G | otal |
|                           | 3**  | 4**  | tal/ | de** | rade | /N** |
|                           |      |      |      |      |      |      |
|                           |      |      | N    | *    | *    |      |
|                           |      |      |      | *3** | *4** |      |
+---------------------------+------+------+------+------+------+------+
| Hypophosphatemia          | 5    |      | 5    |      |      |      |
|                           |      |      | /176 |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hyperuricemia             |      | 1    | 1    |      |      | 20   |
|                           |      |      | /235 |      |      |      |
+---------------------------+------+------+------+------+------+------+
| **Clinical Pharmacology   |      |      |      |      |      |      |
| RA**                      |      |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypercholesterolemia      | 3    |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hyponatremia              | 1    |      |      | 3    |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypokalemia               | 1    |      |      | 1    |      |      |
+---------------------------+------+------+------+------+------+------+
| Hyperkalemia              | 1    | 3    |      | 2    | 2    |      |
+---------------------------+------+------+------+------+------+------+
| Hyperuricemia             |      | 2    |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypercreatinine           | 1    |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypophosphatemia          |      |      |      |      | 1    |      |
+---------------------------+------+------+------+------+------+------+
| ## Adeq                   |      |      |      |      |      |      |
| uate and Well-controlled  |      |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Low hemoglobin            | 8    |      |      | 1    |      |      |
+---------------------------+------+------+------+------+------+------+
| Leukopenia                | 3    |      |      | 1    |      |      |
+---------------------------+------+------+------+------+------+------+
| Lymphocytopenia           | 15   |      |      | 12   |      |      |
+---------------------------+------+------+------+------+------+------+
| Neutropenia               |      | 1    |      |      | 1    |      |
+---------------------------+------+------+------+------+------+------+
| AST elevation             | 1    |      |      | 2    |      |      |
+---------------------------+------+------+------+------+------+------+
| ALT elevation             | 1    |      |      | 2    |      |      |
+---------------------------+------+------+------+------+------+------+
| CK elevation              | 2    |      |      | 1    |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypercholesterolemia      |      |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hyponatremia              |      | 1    |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypernatremia             |      | 1    |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypokalemia               |      |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hyperkalemia              |      | 1    |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hyperuricemia             |      | **20 |      |      | **7  |      |
|                           |      | \*** |      |      | \*** |      |
+---------------------------+------+------+------+------+------+------+
| Hypercreatinine           |      |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
| Hypophosphatemia          |      |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+
|                           |      |      |      |      |      |      |
+---------------------------+------+------+------+------+------+------+

\* Among these 27 patients with hyperuricemia, 12 patients had grade 1
hyperuricemia (\>ULN -- ≤10 mg/dl) and 13 had grade 4 hyperuricemia (≥10
mg/dl) at screening or baseline. Six patients had hyperuricemia
classified as an adverse event. One patient had an episode of gout and
one patient had a kidney stone possibly related to hyperuricemia. There
was no grade 3 hyperuricemia.

**3. Liver Enzymes**

During the adequate and well-controlled studies, sixteen patients (nine
treated with adalimumab and seven treated with placebo) developed AST
and ALT liver enzyme elevations greater than twice the ULN. Overall
between one and four percent of adalimumab-treated patients developed
[\>]{.underline} 2 fold elevation of liver enzymes. This was similar to
the percent of placebo-treated patients with liver enzyme elevations
(Table 84; Table 85).

Four patients with these elevations did not return to normal by the end
of the study or during the open-label continuation studies. Bilirubin
levels were always within normal range and albumin and GGT levels were
not determined for these patients. In two patients, ALT and AST
elevations returned to normal ranges during follow-up periods (one was
taking concomitant MTX). In a third patient, taking concomitant MTX,
these liver enzymes were elevated at baseline and remained elevated. The
fourth patient was eventually diagnosed with primary biliary cirrhosis.
None of these four patients received leflunomide.

One patient with a history of fatty liver developed hepatic necrosis and
died while receiving adalimumab. This patient never had elevation of AST
or ALT. Given the history of liver disease, it is uncertain whether
adalimumab was contributory. Nonetheless, vigilance for additional cases
of hepatotoxicity is warranted.

Table 84 : ISS : Percentage of Patients with AST Elevation Greater Than
Two Times ULN on At Least One Occasion

+--------------+--------+--------+--------+--------+--------+--------+
|              |        | ##     |        |        |        |        |
|              |        | ###### |        |        |        |        |
|              |        |  Adali |        |        |        |        |
|              |        | mumab  |        |        |        |        |
|              |        | Dosage |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| ##           | **Pla  | **20   | **20   | **40   | **40   | **80   |
| ###### Study | cebo** | mg     | mg**   | mg     | mg**   | mg     |
|              |        | q2w**  |        | q2w**  |        | q2w**  |
|              |        |        | **qw** |        | **qw** |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE009**    | 0      | 3      |        | 3      |        | 1      |
| ^1^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE011**    | 1      | 4      | 3      | 2      | 0      |        |
| ^2^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE019**    | 4      |        | 2      | 3      |        |        |
| ^3^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE031**    | 3      |        |        | 4      |        |        |
| ^4^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+

^1^ In this study, all patients were on concomitant MTX.

^2^ In this study, all patients were on no concomitant DMARDs.

^3^ In this study, all patients were on concomitant MTX.

^4^ In this study, all patients were on concomitant standard of care
which could include any combination of DMARDs.

Table 85 : ISS : Percentage of Patients with ALT Elevation Greater Than
Two Times ULN on At Least One Occasion

+--------------+--------+--------+--------+--------+--------+--------+
|              |        | ##     |        |        |        |        |
|              |        | ###### |        |        |        |        |
|              |        |  Adali |        |        |        |        |
|              |        | mumab  |        |        |        |        |
|              |        | Dosage |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| ##           | **Pla  | **20   | **20   | **40   | **40   | **80   |
| ###### Study | cebo** | mg     | mg**   | mg     | mg**   | mg     |
|              |        | q2w**  |        | q2w**  |        | q2w**  |
|              |        |        | **qw** |        | **qw** |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE009**    | 2      | 1      |        | 8      |        | 4      |
| ^1^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE011**    | 2      | 1      | 2      | 3      | 2      |        |
| ^2^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE019**    | 7      |        | 5      | 3      |        |        |
| ^3^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **DE031**    | 2      |        |        | 6      |        |        |
| ^4^          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+

^1^ In this study, all patients were on concomitant MTX.

^2^ In this study, all patients were on no concomitant DMARDs.

^3^ In this study, all patients were on concomitant MTX.

^4^ In this study, all patients were on concomitant standard of care
which could include any combination of DMARDs.

O. Immunogenicity

Concern has been raised about the ability of HAHAs (human anti-human
antibody) to reduce the beneficial effects of biological therapeutic
agents, as well as increase the likelihood of adverse effects.
Therefore, patients were tested at multiple time-points for antibodies
to adalimumab during the 6 to 12 month period of the trials (Table 86).
Six percent of adalimumab-treated patients and less than one percent of
placebo-treated patients developed low-titer neutralizing HAHAs at
titers \> 20 ng/ml at least once during treatment*.*

Table 86 : ISS : Development of HAHAs by randomized treatment in the
adequate and well-controlled studies with (DE009, DE019) and without
(DE011) background MTX

![](media/image41.png){width="5.9375in" height="2.0416666666666665in"}

Patients receiving biweekly dosing developed antibodies more frequently
than those receiving weekly dosing (Table 87).

Table 87 : ISS : Relationship of HAHA Positivity Status to Adalimumab
Frequency

+-----------+------+------+------+------+------+------+------+------+
|           | **Ad |      |      |      |      |      | #    |      |
|           | alim |      |      |      |      |      | ###  |      |
|           | umab |      |      |      |      |      | Plac |      |
|           | Ad   |      |      |      |      |      | ebo  |      |
|           | mini |      |      |      |      |      | {#pl |      |
|           | stra |      |      |      |      |      | aceb |      |
|           | tion |      |      |      |      |      | o-5} |      |
|           | Fre  |      |      |      |      |      |      |      |
|           | quen |      |      |      |      |      | **N  |      |
|           | cy** |      |      |      |      |      | =3   |      |
|           |      |      |      |      |      |      | 72** |      |
+-----------+------+------+------+------+------+------+------+------+
|           | **   |      | **Q2 |      | **A  |      |      |      |
|           | Week |      | wee  |      | ll** |      |      |      |
|           | ly** |      | ks** |      |      |      |      |      |
|           |      |      |      |      | **N  |      |      |      |
|           | **N  |      | **N  |      | =10  |      |      |      |
|           | =    |      | =    |      | 62** |      |      |      |
|           | 4    |      | 6    |      |      |      |      |      |
|           | 27** |      | 35** |      |      |      |      |      |
+-----------+------+------+------+------+------+------+------+------+
|           | n    | \%   | n    | \%   | n    | \%   | n    | \%   |
+-----------+------+------+------+------+------+------+------+------+
| HAHA (+)  | 16   | 4    | **   | *    | 58   | 5    | 2    | 0.5  |
|           |      |      | 42** | *7** |      |      |      |      |
+-----------+------+------+------+------+------+------+------+------+
|           | **20 | 4    | **20 | **   |      |      |      |      |
|           | mg** |      | mg** | 11** |      |      |      |      |
+-----------+------+------+------+------+------+------+------+------+
|           | **40 | 4    | **40 | *    |      |      |      |      |
|           | mg** |      | mg** | *6** |      |      |      |      |
+-----------+------+------+------+------+------+------+------+------+

Patients treated with concomitant methotrexate had a lower rate of
antibody development than patients on adalimumab monotherapy (1% versus
12%) (Table 88).

Table 88 : ISS : Relationship of HAHA Positivity Status to Adalimumab
Concomitant MTX Therapy

+-----------+------+------+------+------+------+------+------+------+
|           | **   |      |      |      |      |      | #    |      |
|           | Adal |      |      |      |      |      | ###  |      |
|           | imum |      |      |      |      |      | Plac |      |
|           | ab** |      |      |      |      |      | ebo  |      |
|           |      |      |      |      |      |      | {#pl |      |
|           |      |      |      |      |      |      | aceb |      |
|           |      |      |      |      |      |      | o-6} |      |
|           |      |      |      |      |      |      |      |      |
|           |      |      |      |      |      |      | **N  |      |
|           |      |      |      |      |      |      | =3   |      |
|           |      |      |      |      |      |      | 72** |      |
+-----------+------+------+------+------+------+------+------+------+
|           | **M  |      | **   |      | **A  |      |      |      |
|           | onot |      | With |      | ll** |      |      |      |
|           | hera |      | M    |      |      |      |      |      |
|           | py** |      | TX** |      | **N  |      |      |      |
|           |      |      |      |      | =10  |      |      |      |
|           | **N  |      | **N  |      | 62** |      |      |      |
|           | =    |      | =    |      |      |      |      |      |
|           | 4    |      | 6    |      |      |      |      |      |
|           | 34** |      | 28** |      |      |      |      |      |
+-----------+------+------+------+------+------+------+------+------+
|           | n    | \%   | n    | \%   | n    | \%   | n    | \%   |
+-----------+------+------+------+------+------+------+------+------+
| HAHA (+)  | **   | **   | *    | *    | 58   | 5    | 2    | 1    |
|           | 54** | 12** | *4** | *1** |      |      |      |      |
+-----------+------+------+------+------+------+------+------+------+

HAHA-positivity was higher among patients treated biweekly with
adalimumab at 20 mg than at 40 mg (Table 89). The long-term
immunogenicity of adalimumab is unknown.

Table 89 : ISS : Relationship of HAHA Positivity Status to Adalimumab
dosage

<table style="width:100%;">
<colgroup>
<col style="width: 16%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="8"><strong>Adalimumab Dosage</strong></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td rowspan="2"></td>
<td colspan="2"><p><strong>20 mg</strong></p>
<p><strong>N = 499</strong></p></td>
<td colspan="2"><p><strong>40 mg</strong></p>
<p><strong>N = 490</strong></p></td>
<td colspan="2"><p><strong>80 mg</strong></p>
<p><strong>N = 73</strong></p></td>
<td colspan="2"><p><strong>All</strong></p>
<p><strong>N =1062</strong></p></td>
<td colspan="2"><h4 id="placebo-7">Placebo</h4>
<p><strong>N =372</strong></p></td>
</tr>
<tr class="odd">
<td>n</td>
<td>%</td>
<td>n</td>
<td>%</td>
<td>n</td>
<td>%</td>
<td>n</td>
<td>%</td>
<td>n</td>
<td>%</td>
</tr>
<tr class="even">
<td rowspan="3">HAHA (+)</td>
<td><strong>31</strong></td>
<td><strong>6</strong></td>
<td><strong>26</strong></td>
<td><strong>5</strong></td>
<td>1</td>
<td>1</td>
<td>58</td>
<td>5</td>
<td>2</td>
<td>0.5</td>
</tr>
<tr class="odd">
<td><strong>Qw</strong></td>
<td><strong>4</strong></td>
<td><strong>Qw</strong></td>
<td><strong>4</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>Q2w</strong></td>
<td><strong>11</strong></td>
<td><strong>Q2w</strong></td>
<td><strong>6</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

At the proposed dosage of 40 mg the ACR 20 response was lower among
antibody-positive patients (30%) than among antibody-negative patients
(50%).

Seven percent (4/58) of HAHA-positive adalimumab-treated patients
withdrew prematurely from Studies DE009, DE011, and DE019 (Table 90).
One of these four patients withdrew due to an AE. The other patients
withdrew due to lack of efficacy (2 patients) and withdrawal of consent
(1 patient). There is no evidence for an increase in incidence of
withdrawals related to the occurrence of HAHA-positivity

Table 90 : ISS : Withdrawal by reason in Studies DE009, DE011 and DE019
by randomized treatment and HAHA status (101)

![](media/image42.png){width="5.997222222222222in"
height="2.8694444444444445in"}

Treatment-emergent AEs were reported in []{.underline}5% of all
adalimumab-treated patients during Study DE011 (Table 91).
HAHA-positivity occurred more frequently in this monotherapy study
without concomitant MTX, but HAHA-positivity was not associated with
clinically meaningful differences in the incidence of treatment-emergent
AEs.

Table 91 : ISS : Overview of treatment-emergent adverse events by HAHA
status in Study DE011

+---------------------------+-------------+------------+--------------+
|                           | **All       |            | **Placebo**  |
|                           | A           |            |              |
|                           | dalimumab** |            | **(N=110)**  |
+---------------------------+-------------+------------+--------------+
|                           | **HAHA      | **HAHA     |              |
|                           | (+)**       | (-)**      |              |
|                           |             |            |              |
|                           | **(N=54)**  | *          |              |
|                           |             | *(N=380)** |              |
+---------------------------+-------------+------------+--------------+
|                           |             |            |              |
+---------------------------+-------------+------------+--------------+
| ## Patients with any      | **N (%)**   | **N (%)**  | **N (%)**    |
+---------------------------+-------------+------------+--------------+
| **AE**                    | 53 (98)     | 376 (99)   | 105 (96)     |
+---------------------------+-------------+------------+--------------+
| **Clinical AE**           | 47 (87)     | 350 (92)   | 92 (84)      |
+---------------------------+-------------+------------+--------------+
| **Laboratory AE**         | **49 (91)** | **342      | **98 (89)**  |
|                           |             | (90)**     |              |
+---------------------------+-------------+------------+--------------+
| **Fatal AE**              | 0 (0)       | 3 (1)      | 1 (1)        |
+---------------------------+-------------+------------+--------------+
| **SAE**                   | 8 (15)      | 54 (14)    | 18 (16)      |
+---------------------------+-------------+------------+--------------+
| **Planned surgery**       | 5 (9)       | 11 (3)     | 3 (3)        |
+---------------------------+-------------+------------+--------------+
| **SAE except planned      | 4 (7)       | 47 (12)    | 15 (14)      |
| surgeries**               |             |            |              |
+---------------------------+-------------+------------+--------------+
| **AE leading to           | 2 (4)       | 25 (7)     | 3 (3)        |
| withdrawal**              |             |            |              |
+---------------------------+-------------+------------+--------------+
| **AE leading to dose      | **6 (11)**  | **55       | **6 (6)**    |
| interruption**            |             | (15)**     |              |
+---------------------------+-------------+------------+--------------+
| **AE leading to dose      | 1 (2)       | 0 (0)      | 0 (0)        |
| reduction**               |             |            |              |
+---------------------------+-------------+------------+--------------+
| **At least severe AE**    | 13 (24)     | 96 (25)    | 25 (23)      |
+---------------------------+-------------+------------+--------------+
| **At least possibly       | 36 (67)     | 257 (68)   | 50 (46)      |
| drug-related AE**         |             |            |              |
+---------------------------+-------------+------------+--------------+
| **Infection**             | **29 (54)** | **178      | **43 (39)**  |
|                           |             | (47)**     |              |
+---------------------------+-------------+------------+--------------+
| **Serious infection**     | 0 (0)       | 11 (3)     | 0 (0)        |
+---------------------------+-------------+------------+--------------+
| **Malignancy**            | 0 (0)       | 5 (1)      | 1 (1)        |
+---------------------------+-------------+------------+--------------+
| **Immunologic reaction**  | 1 (2)       | 3 (1)      | 0 (0)        |
+---------------------------+-------------+------------+--------------+

> P. Impact of Dose on Safety

Based on data from Study DE011, the monotherapy trial, adalimumab 40 mg
administered weekly showed a higher ACR20 than when administered
biweekly, 54% compared to 47%, respectively. The AE rate observed with
the two interim dosing schedules did not show an increased adverse event
rate in patients treated weekly compared to those treated every other
week ().

Table 92 : ISS : Overview of number (Percentage) of patients with
treatment-emergent AEs Subsetted by Dosage (safety set)

![](media/image43.png){width="5.998611111111111in"
height="2.9145833333333333in"}

> Q. Impact of Dose Interruption on Safety

The impact of dose interruption on loss of efficacy and safety was
evaluated in a small group of patients who had single dose interruptions
of either \>70 to ≤ 140 days or \> 140 days (Table 93). The majority of
patients demonstrating an ACR20 prior to an interruption for \>70 to ≤
140 days maintained their ACR20-response. With only four cases with
interruption of \> 140 days, the numbers are too small to draw any
definite conclusion.

Table 93 : ISS : Impact of Dose Interruption on Efficacy

+-----------------+------------+------------+--------------+----------+
| **Duration of   | # AC       |            |              |          |
| Dose            | R20 Respon |            |              |          |
| Interruption**  | se in Rela |            |              |          |
|                 | tion to In |            |              |          |
| **During        | terruption |            |              |          |
| Therapy**       |            |            |              |          |
|                 |            |            |              |          |
| **in Days**     |            |            |              |          |
+-----------------+------------+------------+--------------+----------+
|                 | **Response |            | **Response   |          |
|                 | Prior to   |            | Within First |          |
|                 | Inte       |            | Two Time     |          |
|                 | rruption** |            | points After |          |
|                 |            |            | Restarting** |          |
+-----------------+------------+------------+--------------+----------+
|                 | **         | **         | **Positive** | **Ne     |
|                 | Negative** | Positive** |              | gative** |
+-----------------+------------+------------+--------------+----------+
| **Dose          |            |            |              |          |
| Interruptions   |            |            |              |          |
| During          |            |            |              |          |
| Therapy -       |            |            |              |          |
| Single**        |            |            |              |          |
+-----------------+------------+------------+--------------+----------+
| **\>70 to ≤ 140 |            | **40**     |              | **6      |
| ^a^**           |            |            |              | (15%)**  |
|                 |            |            |              |          |
| (N with         |            |            |              |          |
| data=101)       |            |            |              |          |
+-----------------+------------+------------+--------------+----------+
|                 |            |            | **34 (85%)** |          |
+-----------------+------------+------------+--------------+----------+
|                 | **61**     |            | **21 (34%)** |          |
+-----------------+------------+------------+--------------+----------+
|                 |            |            |              | **40 (   |
|                 |            |            |              | 66%)**   |
+-----------------+------------+------------+--------------+----------+
| **\>140 ^b^**   |            | **4**      |              | **2      |
|                 |            |            |              | (50%)**  |
| (N with         |            |            |              |          |
| data=20)        |            |            |              |          |
+-----------------+------------+------------+--------------+----------+
|                 |            |            | **2 (50%)**  |          |
+-----------------+------------+------------+--------------+----------+
|                 | **16**     |            | **9 (56%)**  |          |
+-----------------+------------+------------+--------------+----------+
|                 |            |            |              | **7      |
|                 |            |            |              | (44%)**  |
+-----------------+------------+------------+--------------+----------+

**^a^** approximately 5 to 10 half-lives

**^b^** approximately 10 half-lives

The types of AEs that occurred before and after dose interruption
appeared to be comparable. In the intravenous portion of the clinical
development program, two patients had systemic infusion reactions
associated with dose interruptions of \>70 to ≤140 days (Table 94). Of
20 Patients having longer dose interruptions (i.e. \>140 days), both in
the intravenous portion and subcutaneous portions of the clinical
development program, they did not have systemic immunologic reactions.

Table 94 : ISS : Impact of Dose Interruption on Safety

+----------------+--------------------------+--------------------------+
| **Patients**   | **\`**                   |                          |
|                |                          |                          |
|                | # Type                   |                          |
|                |  of Immunologic Reaction |                          |
|                |                          |                          |
|                | **(Systemic              |                          |
|                | Anaphylactoid Reaction   |                          |
|                | or Urticaria)**          |                          |
+----------------+--------------------------+--------------------------+
|                | **Before Interruption**  | # After Interruption     |
+----------------+--------------------------+--------------------------+
| # Intraveno    |                          |                          |
| us Portion of  |                          |                          |
| Clinical Devel |                          |                          |
| opment Program |                          |                          |
|                |                          |                          |
| # Int          |                          |                          |
| erruption \>70 |                          |                          |
|  to ≤ 140 Days |                          |                          |
+----------------+--------------------------+--------------------------+
| **Patient \#   | **Fixed drug reaction**  | **Two separate infusion  |
| 53**           |                          | reactions**              |
|                |                          |                          |
|                |                          | **Patient remained on    |
|                |                          | study drug**             |
+----------------+--------------------------+--------------------------+
| **Patient \#   |                          | **Two infusion reactions |
| 85**           |                          | on days 143 and 380.     |
|                |                          | Following second         |
|                |                          | reaction study drug was  |
|                |                          | discontinued.**          |
+----------------+--------------------------+--------------------------+
| # Intraveno    |                          |                          |
| us Portion of  |                          |                          |
| Clinical Devel |                          |                          |
| opment Program |                          |                          |
|                |                          |                          |
| # Interrupt    |                          |                          |
| ion \>140 Days |                          |                          |
+----------------+--------------------------+--------------------------+
| #  None        |                          |                          |
+----------------+--------------------------+--------------------------+
| # Subcutaneo   |                          |                          |
| us Portion of  |                          |                          |
| Clinical Devel |                          |                          |
| opment Program |                          |                          |
+----------------+--------------------------+--------------------------+
| **None**       |                          |                          |
+----------------+--------------------------+--------------------------+

**R.** **Impact of Age on Safety**

In the AWC studies, the exposure-weighted frequency of AEs increased
with increasing age among the elderly in both adalimumab- and
placebo-treated groups (Table 95; Table 96). The rate of SAEs, AEs
leading to withdrawal, AEs leading to dose interruption, severe or
life-threatening/intractable AEs, and serious infections were higher
among patients over age 65 compared to patients under 65 in both the
adalimumab-- and placebo-treatment groups. However, the frequency of
patients with serious infections was highest among adalimumab--treated
patients over age 65. The frequency of patients with malignancies and
fatal AEs, which mainly occurred in the adalimumab-treated group, also
increased with increasing age. Due to the relatively small number of
patients involved, firm conclusions cannot be reached regarding whether
adalimumab increases the relative risk of older patients for these
events.

Table 95: ISS - Overview of Number (Number/100 Patient Years) of
Patients with Treatment --Emergent AEs Subsetted By Age -- Adequate and
Well-Controlled Studies (Safety Set)

![](media/image44.png){width="6.497222222222222in"
height="3.1631944444444446in"}

Table 96 : ISS : Overview of Number (Number of Events/100 Patient Years)
of Patients with Treatment --Emergent AEs Subsetted By Age -- Adequate
and Well-Controlled Studies (Safety Set)

![](media/image45.png){width="6.497222222222222in"
height="2.7784722222222222in"}

**S. Impact of Concomitant Methotrexate on Safety**

In order to determine whether concomitant MTX would increase the
incidence of AEs associated with adalimumab, a comparison was made of
the incidence of AEs with and without concomitant MTX (Table 97). At the
proposed adalimumab dosage of 40 mg biweekly, concomitant MTX did not
appear to increase the incidence of AEs, SAEs, serious infections,
infections, malignancies, or laboratory AEs. However, caution should be
used in interpreting these figures since many of the patients treated
with concomitant MTX were from different trials than the patients not
receiving concomitant MTX. The monotherapy trials were performed in
Europe and the MTX combination trials were performed in the US.
Differences in the overall incidence of adverse events in the different
trials could influence the relative rates shown in Table 97.

Table 97 : ISS : Overview of Adverse Events During Treatment With 40 mg
Every Other Week Adalimumab With and Without MTX (All studies in
patients with RA through March 29, 2002)

+--------------------------------+----+---+--------+----+---+--------+
|                                | ** |   |        |    |   |        |
|                                | Ad |   |        |    |   |        |
|                                | al |   |        |    |   |        |
|                                | im |   |        |    |   |        |
|                                | um |   |        |    |   |        |
|                                | ab |   |        |    |   |        |
|                                | 40 |   |        |    |   |        |
|                                | mg |   |        |    |   |        |
|                                | E  |   |        |    |   |        |
|                                | ve |   |        |    |   |        |
|                                | ry |   |        |    |   |        |
|                                | O  |   |        |    |   |        |
|                                | th |   |        |    |   |        |
|                                | er |   |        |    |   |        |
|                                | We |   |        |    |   |        |
|                                | ek |   |        |    |   |        |
|                                | ** |   |        |    |   |        |
+--------------------------------+----+---+--------+----+---+--------+
|                                | ** |   |        | *  |   |        |
|                                | Wi |   |        | *W |   |        |
|                                | th |   |        | it |   |        |
|                                | M  |   |        | ho |   |        |
|                                | TX |   |        | ut |   |        |
|                                | ** |   |        | M  |   |        |
|                                |    |   |        | TX |   |        |
|                                | ** |   |        | ** |   |        |
|                                | N= |   |        |    |   |        |
|                                | 11 |   |        | ** |   |        |
|                                | 95 |   |        | N= |   |        |
|                                | ** |   |        | 10 |   |        |
|                                |    |   |        | 05 |   |        |
|                                |    |   |        | ** |   |        |
+--------------------------------+----+---+--------+----+---+--------+
| Patients with Any              | *  | * | **N/1  | *  | * | **N/1  |
|                                | *N | * | 00PY** | *N | * | 00PY** |
|                                | ** | % |        | ** | % |        |
|                                |    | * |        |    | * |        |
|                                |    | * |        |    | * |        |
+--------------------------------+----+---+--------+----+---+--------+
| AE                             | 10 | 9 | 89     | 9  | 9 | 96     |
|                                | 92 | 1 |        | 72 | 7 |        |
+--------------------------------+----+---+--------+----+---+--------+
| Clinical AE                    | 10 | 9 | 88     | 9  | 9 | 91     |
|                                | 80 | 0 |        | 18 | 1 |        |
+--------------------------------+----+---+--------+----+---+--------+
| Laboratory AE                  | 2  | 2 | 19     | 7  | 7 | 72     |
|                                | 92 | 4 |        | 30 | 3 |        |
+--------------------------------+----+---+--------+----+---+--------+
| Fatal AE                       | 8  | 1 | 1      | 7  | 1 | 1      |
+--------------------------------+----+---+--------+----+---+--------+
| SAE                            | 2  | 1 | 13     | 2  | 2 | 24     |
|                                | 08 | 7 |        | 45 | 4 |        |
+--------------------------------+----+---+--------+----+---+--------+
| AE leading to withdrawal       | 81 | 7 | 5      | 78 | 8 | 8      |
+--------------------------------+----+---+--------+----+---+--------+
| AE leading to interruption     | 2  | 2 | 16     | 2  | 2 | 24     |
|                                | 58 | 2 |        | 42 | 4 |        |
+--------------------------------+----+---+--------+----+---+--------+
| AE leading to dose reduction   | 3  | \ | \<1    | 1  | \ | \<1    |
|                                |    | < |        |    | < |        |
|                                |    | 1 |        |    | 1 |        |
+--------------------------------+----+---+--------+----+---+--------+
| Sever                          | 2  | 2 | 16     | 3  | 3 | 30     |
| e/Life-threatening/Intractable | 50 | 1 |        | 06 | 0 |        |
| AE                             |    |   |        |    |   |        |
+--------------------------------+----+---+--------+----+---+--------+
| At least possibly drug-related | 5  | 4 | 37     | 6  | 6 | 61     |
| AE                             | 85 | 9 |        | 15 | 1 |        |
+--------------------------------+----+---+--------+----+---+--------+
| Infections (serious and        | 7  | 5 | 48     | 6  | 6 | 59     |
| non-serious)                   | 54 | 3 |        | 01 | 0 |        |
+--------------------------------+----+---+--------+----+---+--------+
| Serious infections             | 45 | 4 | 3      | 38 | 4 | 4      |
+--------------------------------+----+---+--------+----+---+--------+
| Malignancy                     | 32 | 3 | 2      | 21 | 2 | 2      |
+--------------------------------+----+---+--------+----+---+--------+
| Immunologic reaction           | 8  | 1 | 1      | 12 | 1 | 1      |
+--------------------------------+----+---+--------+----+---+--------+

**VII. Financial Disclosure**

The effect of potential financial conflicts of interest on clinical
study results was assessed. Analysis of the financial disclosure forms
provided by sponsor listed no participation in financial arrangements or
financial interests by clinical investigators of adalimumab in the
following clinical studies**:** DEOO1, DEOO3, DEOO4, DEOO5, DE005X,
DEOO7, DEOO9, DEOO9X, DEO11, DEOI5, DEO18, DEOI9, DEO20, DEO24, DEO29
and DE031. In conclusion, results of these studies did not appear to be
influenced by potential financial conflicts of interest.

> **VIII. Overall Summary of Efficacy and Safety**

The clinical development of adalimumab focused on establishing the
therapeutic indications of 1) reducing the signs and symptoms, 2)
inhibiting the progression of structural damage, and 3) improving
health-related quality of life and reducing disability in adult patients
with moderately to severely active RA who have had an incomplete
response to one or more DMARDs. Adalimumab was evaluated in four
clinical studies: DE009, a dose ranging trial, DE011, a monotherapy
trial, DE019, a background MTX trial, and DE031, a background DMARDs
trial (use in a setting comparable to standard rheumatologic care). The
results of the randomized efficacy studies are consistent in showing
efficacy of adalimumab in reducing the signs and symptoms of rheumatoid
arthritis as measured by the ACR20 response. Efficacy of adalimumab was
observed in all patient subsets based on baseline demographics, baseline
disease activity and baseline prognostic factors. ACR50 and ACR70
responses higher than with placebo were also achieved.

Efficacy of adalimumab was seen both for monotherapy (study DE011),
combination therapy with MTX (study DE019), and combination with a
variety of other DMARDs that patients were already receiving (study
DE031). The optimal dose of adalimumab is 40 mg sc every other week when
given in combination with MTX. Higher doses were not more effective
(study DE009). In contrast, for monotherapy, although adalimumab 40 mg
every other week was effective (43% ACR20 responses at 6 months), 40 mg
weekly was associated with higher response rates (54% ACR20 responses at
6 months) (study DE011). Of note, the point estimates of the response
rates for adalimumab 40 mg every other week with MTX were higher (63%
ACR20 responses at 6 months -- study DE019) than with monotherapy (46 %
ACR20 responses at 6 months -- study DE011). Although comparing results
between studies must be done with caution, the higher responses with the
adalimumab-MTX combination may be due to inhibition of anti-adalimumab
antibody formation by MTX.

Improvement was seen on all the components of the ACR response criteria.
Separation between the responses of adalimumab- and placebo-treated
patients occurred as early as Week 2 and was maintained through Week 52.
In study DE019, adalimumab-treated patients experienced a lower rate of
progression in structural damage as measured by the modified Sharpe
score than placebo-treated patients. In addition, adalimumab-treated
patients experienced improvement in physical function as measured by the
disability index of the HAQ compared to placebo over 52 weeks. However,
as stated in the RA Guidance Document, attaining a claim of Improvement
in Physical Function requires data demonstrating sustained improvement
in the HAQ out to 2 years.

Overall, the short- and long-term safety and tolerability of adalimumab
has been demonstrated in a large database of RA patients exposed to the
drug for up to 4 years. Adalimumab, at the proposed dosage of 40 mg
biweekly, was generally well tolerated, except for the increased
occurrence of injection site reactions and pain, upper respiratory
infections, abnormal laboratory tests, and rashes. Three categories of
events of special interest were observed to occur at a higher frequency
among adalimumab-treated patients compared to placebo: deaths,
lymphomas, and infections (serious and non-serious).

Twenty-four deaths were observed among the adalimumab-treated patients
in the clinical development program. Since the trials included a
significant number of older patients, 22% age 65 to 75 and 5% over age
75, some deaths were expected Even though the majority of patients
enrolled in these studies were females, the majority of the deaths
occurred in male subjects. The most frequent categories of death were
cardiovascular, malignancy, infections, and gastrointestinal.

Since most of the patient exposure was from open-label extension
studies, there are no concurrent controls for comparison. To provide an
estimate as to whether\` the mortality rate is higher than expected, the
mortality rate was compared to that predicted based on sex and
age-matched rates in the general US population.

Determination of the Standardized Mortality Rate (SMR) for comparison of
the observed death rate to the age-adjusted expected frequency of deaths
for this population suggested that the death rate for males was higher
(SMR 1.38 \[CI, 0.72,2.44\]) and the death rate for females was lower
than expected (SMR 0.45 \[CI, 0.22, 0.83\]). Whereas the confidence
interval for male deaths overlapped 'one,' the male mortality rate and
overall mortality rate were within the expected range. The SMR for the
whole group of adalimumab-treated patients was 0.72 \[CI, 0.46, 1.05\].
These data do not indicate a higher death rate with adalimumab
treatment. Collection of additional data with longer-term exposure is
warranted, particularly for male patients.

A total of ten lymphomas, primarily Non Hodgkin's lymphoma, was observed
in patients treated with adalimumab. The observed SIR (ratio of observed
rate to age-adjusted expected frequency) for all lymphomas was 5.4 (95%
CI, 2.6, 10.0) compared to the general population. The increased
incidence of lymphomas observed among these adalimumab-treated patients
has raised concerns about whether adalimumab increases the risk of
development of lymphomas. Published literature suggests that RA patients
have an approximately 2-fold higher risk of lymphoma than the general
population. Furthermore, RA patients with highly active disease have an
even greater risk of lymphomas, irrespective of their treatment, in the
same range as the SIR reported for adalimumab-treated patients. Analysis
of the time-to-onset of the cases of lymphoma seen with adalimumab did
not provide evidence of a relationship to duration of adalimumab
therapy. Available data are insufficient to determine whether adalimumab
increases the incidence of lymphomas. Continued monitoring of
adalimumab-treated patients is necessary to quantify the role of
adalimumab, if any, in contributing to the observed higher incidence of
lymphomas than in the general population.

Since the introduction of TNF blocking agents, which affect host
defenses by modulating cellular immune responses, the Agency has been
concerned about an increased risk of serious infections among
anti-TNF-treated patients. Patients treated with adalimumab experienced
more frequent serious infections than did placebo-treated patients (4.2
vs. 1.9 per 100 patient-years). The most common organs affected by
serious infections among adalimumab-treated patients were pulmonary,
musculoskeletal, skin, gastrointestinal, and genitourinary. Two patients
died and 13 patients withdrew from studies as a result of serious
infections. In addition, thirteen cases of tuberculosis (TB) and six
cases of invasive opportunistic fungal infections were observed.
Implementation of pre-treatment screening with intradermal PPD in the
US, chest x-rays in Europe, and appropriate prophylactic
anti-tuberculosis treatment in accordance with CDC Guidelines was
associated with a reduction in the rate of active TB. However, other
variables may have also contributed to the lower rate of TB later in the
clinical development program, including less exposure to higher doses of
adalimumab and possibly recruitment of fewer patients at high risk of
latent TB infection.

For both adalimumab- and placebo-treated patients, the rate of serious
infections and deaths due to serious infections were lower among
patients \<65 years of age. Increasing age among adalimumab-treated
patients was associated with an increased occurrence of malignancies,
SAEs, AEs leading to withdrawals, and AEs resulting in dose interruption
compared to age-matched placebo-treated patients. The percentage of
patients with fatal AEs, which only occurred in the adalimumab--treated
group, was also higher with advancing age.

In summary, adalimumab treatment has demonstrated substantial efficacy,
both for signs and symptoms as well as for progression of structural
damage to joints and for improvement in disability for up to 12 months.
Uncommon, but serious adverse events were observed in adalimumab-treated
patients. Overall, adalimumab has shown a favorable benefit to risk
profile when administered subcutaneously at the recommended dose of 40
mg every other week, and the higher dose of 40 mg weekly, either alone
or in combination with methotrexate or other DMARDs.

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