Kineret (anakinra)\
(Recombinant Methionyl Human Interleukin-1 Receptor Antagonist)

FDA Arthritis Drugs Advisory Committee\
Briefing Package

Meeting Date: 16 August 2001\
Document Date: 17 July 2001

Volume 1 of 1

Amgen Inc.\
One Amgen Center Drive\
Thousand Oaks‚ CA 91320-1799

TABLE OF CONTENTS

[1. Scientific Rationale 5](#scientific-rationale)

[2. Product Description 6](#product-description)

[2.1 What is Kineret (anakinra) 6](#what-is-kineret-anakinra)

[2.2 Overview of the Clinical Development Program
6](#overview-of-the-clinical-development-program)

[2.3 Proposed Indication and Dose 8](#proposed-indication-and-dose)

[2.4 Subject Exposure 8](#subject-exposure)

[2.5 Clinical Trial Data for Licensure
10](#clinical-trial-data-for-licensure)

[2.6 Content of the Briefing Package
11](#content-of-the-briefing-package)

[3. Nonclinical Pharmacology, Pharmacokinetics, and Toxicology
12](#nonclinical-pharmacology-pharmacokinetics-and-toxicology)

[3.1 Pharmacology 12](#pharmacology)

[3.1.1 Role of IL-1 in Rheumatoid Arthritis
12](#role-of-il-1-in-rheumatoid-arthritis)

[3.1.2 Effects of Anakinra in Animal Models of Arthritis
13](#effects-of-anakinra-in-animal-models-of-arthritis)

[3.1.3 Effects of Anakinra Co-administered With Other Therapies
16](#effects-of-anakinra-co-administered-with-other-therapies)

[3.2 Nonclinical Pharmacokinetics of Anakinra
18](#nonclinical-pharmacokinetics-of-anakinra)

[3.3 Toxicology 18](#toxicology)

[3.4 Summary of Nonclinical Studies 20](#summary-of-nonclinical-studies)

[4. Clinical Data 21](#clinical-data)

[4.1 Introduction 21](#introduction)

[4.2 Human Pharmacokinetics and Bioavailability
22](#human-pharmacokinetics-and-bioavailability)

[4.3 Placebo-controlled Clinical Trials in Rheumatoid Arthritis
24](#placebo-controlled-clinical-trials-in-rheumatoid-arthritis)

[4.3.1 Study Designs: Placebo-controlled Trials
24](#study-designs-placebo-controlled-trials)

[4.3.2 Subject Disposition and Baseline Characteristics
36](#subject-disposition-and-baseline-characteristics)

[4.4 Clinical Data - Efficacy 40](#clinical-data---efficacy)

[4.4.1 Signs and Symptoms Data 40](#signs-and-symptoms-data)

[4.4.2 Monotherapy Study (0560): Radiographic Data
61](#monotherapy-study-0560-radiographic-data)

[4.4.3 Summary of Efficacy 70](#summary-of-efficacy)

[4.5 Clinical Data - Safety 72](#clinical-data---safety)

[4.5.1 Introduction 72](#introduction-1)

[4.5.2 Exposure for Safety Analyses 76](#exposure-for-safety-analyses)

[4.5.3 Adverse Events 77](#adverse-events)

[4.5.4 Serious Adverse Events 82](#serious-adverse-events)

[4.5.5 Deaths 86](#deaths)

[4.5.6 Infectious Events 94](#infectious-events)

[4.5.7 Malignancies 107](#malignancies)

[4.5.8 Adverse Events By Gender 114](#adverse-events-by-gender)

[4.5.9 Adverse Events By Age 114](#adverse-events-by-age)

[4.5.10 Laboratory Parameters 115](#laboratory-parameters)

[4.5.11 Antibodies 125](#antibodies)

[4.5.12 Anakinra Combination With Etanercept: Study 20000125
128](#anakinra-combination-with-etanercept-study-20000125)

[4.5.13 Overall Adverse Event Profile
131](#overall-adverse-event-profile)

[4.5.14 Summary of Safety 134](#summary-of-safety)

[5. Risk/Benefit Assessment 136](#riskbenefit-assessment)

[5.1 Proposed Indication 138](#proposed-indication)

[6. References 139](#references)

**LIST OF APPENDICES**

**Appendix 4-1:** Study 990145 -- LOE Designation

**Appendix 4-2:** Study 0560 -- Week 24 ACR~20~ Response by ISRs

**Appendix 4-3:** Study 0560 -- Sustained Week 24 ACR~20~ Response by
ISRs

**Appendix 4-4:** Study 960180 -- ACR Components for Lower Anakinra
Doses

**Appendix 4-5:** Study 960180 -- Week 12 ACR~20~ Response by ISRs

**Appendix 4-6:** Study 960180 -- Week 24 ACR~20~ Response by ISRs

**Appendix 4-7:** Study 960180 -- Sustained Week 24 ACR~20~ Response by
ISRs

**Appendix 4-8:** Study 990145 -- Week 24 Changes in ACR Components

**Appendix 4-9:** Randomized, Placebo-controlled Studies - AEs

**Appendix 4-10:** SAEs for Randomized, Placebo-controlled Studies

**Appendix 4-11:** Narratives - Deaths

**Appendix 4-12:** Withdrawals due to AES in Randomized,
Placebo-controlled Studies

**Appendix 4-13:** Infections by Preferred Term for Randomized,
Placebo-controlled Studies

**Appendix 4-14:** WHO Toxicity Grading Scales for Laboratory Parameters

# Scientific Rationale

Studies of the pathogenesis of rheumatoid arthritis (RA), in both
experimental animal models and clinical settings, have established a
critical role for the pro-inflammatory cytokine, interleukin-1
(IL-1),^1,2,3^ in tissue remodeling and inflammation. Evidence linking
IL-1 to the pathogenesis of RA is strong. A correlation has been
reported between IL-1 concentrations in the plasma of patients with RA
and the activity of the disease.^4^ The appearance of IL-1 in synovial
fluid from RA patients seems to correspond with acute inflammation of
the joints, whether due to exacerbated symptoms or joint trauma.^5,6^
Production of IL-1 in vitro by explanted synovial tissues from patients
with RA has been positively correlated with arthroscopic results that
quantify the extent of inflammation.^7^ Therapies inhibiting the effects
of IL-1 should provide benefit to patients by relieving signs and
symptoms of the disease and retarding structural damage. Amgen's
anakinra is such a therapy.

Data from animal models support the hypothesis that a therapeutic agent
specifically designed to inhibit IL-1 could provide benefit to patients.
The role of IL-1 in cartilage destruction was demonstrated in mice with
antigen-induced arthritis by administration of a neutralizing antibody
to IL-1. This therapeutic intervention prevented IL-1 induced reduction
in cartilage proteoglycan synthesis^8^ and was able to maintain
chondrocyte proteoglycan synthesis in antigen-rechallenged joints.^9^
When treated with an antibody to IL-1, mice with type II
collagen-induced arthritis showed profound amelioration of both
established and developing disease.^10-13^

A naturally occurring interleukin-1 receptor antagonist (IL-1Ra)
modulates the activity of IL-1 in patients.^14-16^ Both IL-1 and IL-1Ra
have been identified in the synovial fluid and the synovial sublining of
patients with RA or osteoarthritis (OA).^15^ The ratio of IL-1Ra to IL-1
in synovial cells of patients with RA is relatively low, and it is
thought that this ratio is too low to block IL-1 effects.^17^ These
findings indicate that the balance between IL-1Ra and IL-1 is important
in determining disease outcome and suggest that raising levels of IL-1Ra
in patients with RA may provide a therapeutic benefit.

# Product Description

## What is Kineret (anakinra)

Kineret (anakinra; r-met Hu-IL-1ra) is Amgen's recombinant form of
IL-1Ra. It is a protein manufactured in *E coli* using recombinant DNA
technology. The protein consists of 153 amino acids with an approximate
molecular weight of 17.3 kD. Anakinra is identical to the naturally
occurring form of IL-1Ra except for the addition of an N-terminal
methionine residue. Throughout this document anakinra will be used to
distinguish Amgen's recombinant protein from the naturally occurring
form of IL-1Ra.

Anakinra has a unique mechanism of action. By binding to the IL-1 Type I
receptor (IL-1RI), it competitively prevents IL-1 binding. Furthermore,
because anakinra bound to\
IL-RI does not recruit the IL-1R accessory protein (IL-1R AcP), no
signal transduction occurs.

By specifically inhibiting the effects of IL-1, anakinra is the first RA
therapy that targets IL-1 inhibition, thus providing patients with a
novel therapeutic option that can relieve signs and symptoms of RA.

## Overview of the Clinical Development Program

A total of 19 clinical trials (including extension trials and studies in
healthy volunteers) constitute the clinical development program for
anakinra in the RA indication\
(Figure 1-1). In addition, a single-arm, open label study of anakinra in
combination with etanercept (20000125) has recently been completed, and
a study in subjects with juvenile RA is ongoing.

Among these, 5 randomized, placebo-controlled trials support the overall
risk-benefit profile for reduction of the signs and symptoms of RA
(Table 1-1). The Monotherapy Study (0560), the Methotrexate (MTX)
Combination Study (960180) and the Low Dose Monotherapy Study (960182)
were included in the BLA submission in December 1999. Additional data
from the Safety Study (990757), and the Confirmatory Efficacy Study
(990145) provide confirmatory safety and efficacy data at the proposed
dose of 100 mg/day. Data from 5 randomized, placebo-controlled trials
(Table 1-1) will be discussed in detail in this briefing package. Key
safety information from the remaining supportive trials (consisting of
clinical pharmacology, dose-ranging, dose-frequency, and active
treatment extension trials) will also be summarized.

Figure 1-1. Anakinra Clinical Trials in Rheumatoid Arthritis

*Table 1-1: Five Randomized, Placebo-Controlled Trials in RA*

  ----------- ------------------------------ ------------------------- ------------
  **Study**   **Description**                **Daily Doses of          **N**
                                             Anakinra**                

  0560        Monotherapy Study              0, 30, 75, 150 mg         472

  960182      Low Dose Monotherapy Study     0, 2.5, 10, 30 mg         141

  960180      MTX Combination Study          0, 0.04, 0.1, 0.4, 1.0,   419
                                             2.0 mg/kg                 

  990145      Confirmatory Efficacy Study    0, 100 mg                 501

  990757      Safety Study                   0, 100 mg                 1399

                                             ***Total***               ***2932***
  ----------- ------------------------------ ------------------------- ------------

N = Number of subjects who received at least 1 dose of study drug

As indicated in Figure 1-1, most studies had "extensions" allowing
subjects to continue treatment. All extension trials used active drug,
and all but study 0564 (extension to 0560) were open label. Study 0564
was blinded to dose and prior treatment group as described later in
Section 4.4.2.3.

## Proposed Indication and Dose

The proposed indication is as follows: "Kineret (anakinra) is indicated
for the reduction in signs and symptoms of active rheumatoid arthritis,
in subjects 18 years of age or older. Kineret (anakinra) can be used
alone or in combination with other disease-modifying antirheumatic
drugs."

The dose proposed for marketing is a fixed dose of 100 mg administered
by daily subcutaneous (SC) injection. The 100 mg/day fixed dose was
prospectively tested in 2 large, randomized, placebo-controlled clinical
trials (the Safety Study \[990757\] and the Confirmatory Efficacy Study
\[990145\]).

## Subject Exposure 

The anakinra development program in RA includes over 3000 RA subjects,
of whom 2606 were treated with anakinra in the 5 randomized,
placebo-controlled RA studies, the extensions and other supportive and
clinical pharmacology studies (Table 2-1).

Table 2‑1. RA Subjects in Anakinra Clinical Trials

+-------------------------------------+--------------+-----------------+
|                                     | Number of    |                 |
|                                     | Subjects     |                 |
+-------------------------------------+--------------+-----------------+
|                                     | Placebo      | Anakinra        |
+-------------------------------------+--------------+-----------------+
|                                     |              |                 |
+-------------------------------------+--------------+-----------------+
| Randomized placebo-controlled       |              |                 |
+-------------------------------------+--------------+-----------------+
| studies and extensions              | 759          | 2332            |
+-------------------------------------+--------------+-----------------+
|                                     |              |                 |
+-------------------------------------+--------------+-----------------+
| Supportive studies                  | 3            | 199             |
+-------------------------------------+--------------+-----------------+
|                                     |              |                 |
+-------------------------------------+--------------+-----------------+
| Pharmacokinetic studies             | 15           | 75              |
+-------------------------------------+--------------+-----------------+
|                                     |              |                 |
+-------------------------------------+--------------+-----------------+
| Total                               | 777          | 2606            |
+-------------------------------------+--------------+-----------------+
| Includes studies 0501, 0502, 0505,  |              |                 |
| 0560, 0564 and extensions, 960180,  |              |                 |
| 960181, 960182, 970102, 970189,     |              |                 |
| 980220, 990145, and 990757.         |              |                 |
+-------------------------------------+--------------+-----------------+
| Includes 6-month exposure for       |              |                 |
| anakinra subjects in studies 990145 |              |                 |
| (N = 250) and 990757 (N = 1116).    |              |                 |
| For all other studies cut-off date  |              |                 |
| was 15 November 2000.               |              |                 |
|                                     |              |                 |
| /stat/il1ra/fda_brfpkg/analysi      |              |                 |
| s/safety/statfiles/tables/t_exp.sas |              |                 |
|                                     |              |                 |
| Output: t_exp.rtf (generated        |              |                 |
| 25JUN2001)                          |              |                 |
+-------------------------------------+--------------+-----------------+

As shown in Table 2-2, a total of 1379 RA subjects have received
anakinra for at least 6 months and 237 subjects have been treated for at
least 12 months at or above the proposed marketed dose of 100 mg/day.
These numbers exceed ICH exposure guidelines for drugs intended for
long-term treatment of chronic diseases.

An additional 2100 subjects have participated in trials in a variety of
non-RA clinical settings including sepsis, asthma, ulcerative colitis,
chronic myelogenous leukemia (CML), graft versus host disease (GVHD),
and psoriasis.

Table 2‑2. Duration of Exposure in RA Subjects

+---+-------------------------------+---------------+-----------------+---+
|   |                               | Number of     |                 |   |
|   |                               | Subjects      |                 |   |
+---+-------------------------------+---------------+-----------------+---+
|   |                               |               | All Anakinra    |   |
+---+-------------------------------+---------------+-----------------+---+
|   |                               | ≥ 100 mg      | Doses           |   |
+---+-------------------------------+---------------+-----------------+---+
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+---+-------------------------------+---------------+-----------------+---+
|   | \< 6 months                   | 496           | 794             |   |
+---+-------------------------------+---------------+-----------------+---+
|   | ≥ 6 months                    | 1379          | 1812            |   |
+---+-------------------------------+---------------+-----------------+---+
|   | ≥ 1 year                      | 237           | 570             |   |
+---+-------------------------------+---------------+-----------------+---+
|   | ≥ 2 years                     | 77            | 365             |   |
+---+-------------------------------+---------------+-----------------+---+
|   | ≥ 3 years                     | 26            | 167             |   |
+---+-------------------------------+---------------+-----------------+---+
|   | ≥ 4 years                     | 13            | 41              |   |
+---+-------------------------------+---------------+-----------------+---+
|   | ≥ 5 years                     | 5             | 19              |   |
+---+-------------------------------+---------------+-----------------+---+
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+---+-------------------------------+---------------+-----------------+---+

## Clinical Trial Data for Licensure

Amgen filed a Biologics License Application (BLA) in December 1999. The
core clinical data package for the BLA consisted of studies 0560, 960182
and 960180.

A study to assess the safety of combining anakinra with etanercept
(20000125) was completed in March 2001. In order to meet the
requirements of FDA's Pediatric Rule, a trial in subjects with juvenile
RA (JRA; 990758) was initiated; this study is in progress and remains
blinded.

In response to CBER's Complete Review letter, additional safety and
efficacy data from the Confirmatory Efficacy Study (990145) and safety
data from the large Safety Study (990757) were submitted (additional
1900 subjects evaluated for 24 weeks) and included signs and symptoms
data for 501 subjects participating in the Confirmatory Efficacy Study
(990145). In May 2001, safety data from the anakinra/etanercept
combination study (20000125; N = 58) were submitted to CBER upon
request.

## Content of the Briefing Package

This package will discuss in detail the scientific rationale for
developing anakinra for the treatment of the signs and symptoms of RA,
as well as the safety and efficacy data from the 5 placebo-controlled
trials depicted in Table 1-1. The data support the following
conclusions:

-   anakinra is the first therapy for RA that targets IL-1 inhibition

-   there is extensive clinical experience with anakinra in RA patients

-   signs and symptoms of RA are improved with anakinra therapy

-   anakinra's effects occur early and are sustained

-   effects on the signs and symptoms of RA are consistent across
    different patient populations

-   anakinra slows disease progression assessed radiographically, with
    effects apparent at 24 weeks, supporting its use in the treatment of
    RA

-   anakinra has a favorable risk-benefit profile

# Nonclinical Pharmacology, Pharmacokinetics, and Toxicology

## Pharmacology

Interleukin-1 (IL-1) is a key mediator of immune and inflammatory
processes.^18,19^ IL-1 mediates inflammation via recruitment of
neutrophils into the joint, activation of macrophages, and stimulation
of T- and B-cell growth and differentiation. Demonstrated effects of
IL-1 include increased production of cytokines and chemokines by
T-cells, macrophages, and several mesenchymal cells, increased
production of nitric oxide, prostaglandin and collagenase by fibroblasts
and chondrocytes, increased production of adhesion proteins by vascular
endothelium, and release of histamine and thromboxane. IL-1 is
synthesized by many cell types, including circulating leukocytes such as
neutrophils, monocytes, and macrophages, and tissue cells such as
synoviocytes.

There are three members of the IL-1 family (IL-1α, IL-1β, and
interleukin-1 receptor antagonist \[IL-1Ra\]) that bind to interleukin-1
receptor type I (IL-1RI) with similar affinities. When present in
excess, IL-1Ra blocks the association of IL-1α or IL-1β with IL-1RI or
interleukin-1 receptor type II (IL-1RII). IL-1Ra binding to IL-1R does
not allow association of the IL-1R with IL-1R-accessory protein (IL-1R
AcP). Since this complex formation is required for IL-1 signaling,
IL-1Ra binding to IL-1R is incapable of initiating signaling events and
thus IL-1Ra has no agonist activity. ^21,22,56^

### Role of IL-1 in Rheumatoid Arthritis

Rheumatoid arthritis is a systemic inflammatory autoimmune disorder of
unknown etiology, although it is thought to be mediated by
antigen-driven T-cells and macrophages that produce proinflammatory
cytokines such as IL-1 and tumor necrosis factor-alpha
(TNFα).^2,16,23-26^ The evidence linking IL-1 to RA is
compelling.^27,28^ In animals, direct injection of IL-1 into joints is
arthritogenic and causes transient synovitis.^20,29^ Moreover,
continuous infusion of IL-1α into knee joints of rabbits resulted in an
arthritis with signs of both acute (serous and fibrinous exudation,
polymorphonuclear cell infiltration) as well as chronic (synovial cell
proliferation and fibrosis, pannus formation, cartilage and bone
erosion) inflammation.^30^ Similarly, constitutive intra-articular
expression of human IL-1β following gene transfer to rabbit synovium
produces all major pathologies of RA.^31^ Systemic administration of\
IL-1 enhances the incidence and severity of arthritis in several animal
models of inflammatory arthritis. For example, IL-1 can serve as an
adjuvant in murine arthritis models by greatly enhancing the synovial
inflammatory response.^32,33^ Furthermore, intra-articular injection of
IL-1 during the chronic phase of murine antigen-induced arthritis
results in exacerbation of the disease.^8^ In addition, IL-1 is found in
the plasma and synovial fluid of RA patients, and a correlation has been
reported between IL-1 concentrations in the plasma and the activity of
the disease^4^. The appearance of IL-1 in synovial fluid from RA
patients seems to correspond with acute inflammation of the joints,
whether due to exacerbated symptoms or joint traumatization.^5,6^
Production of\
IL-1 in vitro by explanted synovial tissues from RA patients has been
correlated with arthroscopic results indicating the extent of
inflammation.^7^

IL-1 is a potent stimulator of synoviocytes, chondrocytes, and
osteoblasts. Upon exposure to IL-1, fibroblast-like synoviocytes
proliferate and produce prostaglandins as well as metalloproteinases
such as collagenases and stromelysin.^34^ Thus, IL-1 activates effector
molecules responsible for joint destruction in addition to its
proinflammatory effects. IL-1 inhibits proteoglycan synthesis and
stimulates collagen breakdown by chondrocytes.^8,9^ Increased RANK
(receptor activator of NFκB) ligand production from IL-1-stimulated
osteoblasts leads to osteoclast activation and proliferation, resulting
in enhanced bone resorption.^35,36^

In addition to IL-1, IL-1Ra also has been identified in the synovial
fluid and synovial sublining of RA and OA patients.^15^ Studies of
synovial tissue mRNA have shown that the IL-1Ra gene is expressed in RA
synovium.^37^

### Effects of Anakinra in Animal Models of Arthritis

Anakinra was evaluated for its effects on inflammation and cartilage and
bone destruction in several animal models of arthritis (Table 3-3).
Representative data from the collagen-induced arthritis model in rats
are shown in Figure 3-2. Immunization of rats with bovine type II
collagen causes an immunologically mediated polyarthritis with
histologic features resembling those of RA in humans. Principal lesions
include mononuclear cell inflammation, pannus, cartilage degeneration,
and bone destruction. Onset of the clinical signs of the disease occurs
on days 13 to 15. In female Lewis rats, continuous SC infusion of 0.2 to
5 mg/kg/hour anakinra, initiated after onset of clinical signs of
disease resulted in significant inhibition of arthritis (as assessed by
paw swelling), with approximately 90% inhibition at the 5-mg/kg/hour
dose (Figure 3-2).

Table 3‑3. Anakinra Treatment: Animal Models of Arthritis

+--------+----+---------+-------+-------+---+-----------+-----------+
| **     | *  | **Trea  | **D   | *     | * |           | **Re      |
| Animal | *S | tment** | ose** | *Infl | * |           | ference** |
| M      | pe |         |       | ammat | B |           |           |
| odel** | ci |         |       | ion** | o |           |           |
|        | es |         |       |       | n |           |           |
|        | ** |         |       | **%   | e |           |           |
|        |    |         |       | In    | a |           |           |
|        |    |         |       | hibit | n |           |           |
|        |    |         |       | ion** | d |           |           |
|        |    |         |       |       | C |           |           |
|        |    |         |       |       | a |           |           |
|        |    |         |       |       | r |           |           |
|        |    |         |       |       | t |           |           |
|        |    |         |       |       | i |           |           |
|        |    |         |       |       | l |           |           |
|        |    |         |       |       | a |           |           |
|        |    |         |       |       | g |           |           |
|        |    |         |       |       | e |           |           |
|        |    |         |       |       | E |           |           |
|        |    |         |       |       | f |           |           |
|        |    |         |       |       | f |           |           |
|        |    |         |       |       | e |           |           |
|        |    |         |       |       | c |           |           |
|        |    |         |       |       | t |           |           |
|        |    |         |       |       | s |           |           |
|        |    |         |       |       | \ |           |           |
|        |    |         |       |       | * |           |           |
|        |    |         |       |       | * |           |           |
|        |    |         |       |       | * |           |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| My     | R  | SC CI   | 5     | 27%   | 7 | I         | Feige et  |
| cobact | at | for     | mg/   |       | 4 | nhibition | al.       |
| eria-i |    |         | kg/hr | 33%   | % | of bone   | (         |
| nduced |    | 7 days  |       |       |   | mineral   | 2000)^38^ |
| ad     |    | after   | 1     | 13%   | 7 | density   |           |
| juvant |    | onset   | mg/   |       | 3 | loss      |           |
| art    |    | of      | kg/hr |       | % |           |           |
| hritis |    | c       |       |       |   |           |           |
|        |    | linical | 0.2   |       | 2 |           |           |
|        |    | signs   | mg/   |       | 6 |           |           |
|        |    |         | kg/hr |       | % |           |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| Li     | R  | SC CI   | 10    | 18%   | 7 | I         | Bendele   |
| poidal | at | for     | mg/   |       | 9 | nhibition | et al.    |
| a      |    |         | kg/hr | 18%   | % | of bone   | (1999     |
| mine-i |    | 7 days  |       |       |   | r         | ;498)^39^ |
| nduced |    | after   | 5     | 29%   | 7 | esorption |           |
| ad     |    | onset   | mg/   |       | 9 |           |           |
| juvant |    | of      | kg/hr | 12%   | % |           |           |
| art    |    | c       |       |       |   |           |           |
| hritis |    | linical | 2.5   |       | 8 |           |           |
|        |    | signs   | mg/   |       | 5 |           |           |
|        |    |         | kg/hr |       | % |           |           |
|        |    |         |       |       |   |           |           |
|        |    |         | 1     |       | 4 |           |           |
|        |    |         | mg/   |       | 9 |           |           |
|        |    |         | kg/hr |       | % |           |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| Coll   | R  | SC CI   | 5     | 90%   | 8 | I         | Bendele   |
| agen-i | at | for     | mg/   |       | 9 | nhibition | et al.    |
| nduced |    |         | kg/hr | 53%   | % | of        | (1999)    |
| art    |    | 7 days  |       |       |   | his       | ^39^      |
| hritis |    | after   | 1     | 32%   | 5 | tological |           |
|        |    | onset   | mg/   |       | 4 | scores    |           |
|        |    | of      | kg/hr |       | % | (pannus,  |           |
|        |    | c       |       |       |   | cartilage |           |
|        |    | linical | 0.2   |       | 2 | damage,   |           |
|        |    | signs   | mg/   |       | 7 | bone      |           |
|        |    |         | kg/hr |       | % | damage)   |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| Coll   | R  | Daily   | 100   | 74%   | 7 | I         | Bendele   |
| agen-i | at |         | mg/kg |       | 5 | nhibition | et al.    |
| nduced |    | SC      | QD    |       | % | of        | (         |
| art    |    | in      |       |       |   | his       | 1998)^40^ |
| hritis |    | jection |       |       |   | tological |           |
|        |    | in      |       |       |   | scores    |           |
|        |    | Hya     |       |       |   | pannus,   |           |
|        |    | luronic |       |       |   | cartilage |           |
|        |    | Acid    |       |       |   |           |           |
|        |    | for 7   |       |       |   | damage,   |           |
|        |    | days    |       |       |   | bone      |           |
|        |    | after   |       |       |   | damage)   |           |
|        |    | onset   |       |       |   |           |           |
|        |    | of      |       |       |   |           |           |
|        |    | c       |       |       |   |           |           |
|        |    | linical |       |       |   |           |           |
|        |    | signs   |       |       |   |           |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| S      | R  | SC CI   | 5     | 89%   | \ | Not       | Amgen,    |
| trepto | at | for 7   | mg/   |       | - | examined  | Inc.,\    |
| coccal |    | days    | kg/hr | 87%   | - |           | data on   |
| cell   |    | be      |       |       |   |           | file SCW2 |
| wall-i |    | ginning | 1     | 30%   |   |           |           |
| nduced |    | 1 day   | mg/   |       |   |           |           |
|        |    | before  | kg/hr |       |   |           |           |
| art    |    | react   |       |       |   |           |           |
| hritis |    | ivation | 0.2   |       |   |           |           |
|        |    |         | mg/   |       |   |           |           |
|        |    |         | kg/hr |       |   |           |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| S      | R  | Daily   | 8     | \~55% | 1 | I         | Schwab et |
| trepto | at |         | mg/kg |       | 1 | nhibition | al.       |
| coccal |    | SC      | BID   | 55%   | % | of        | (         |
| cell   |    | in      |       |       |   | his       | 1991)^41^ |
| wall-i |    | jection | 2     |       | 6 | tological |           |
| nduced |    | for 4   | mg/kg |       | 3 | scores    |           |
|        |    | days    | QID   |       | % | (s        |           |
| art    |    | be      |       |       |   | ynovitis, |           |
| hritis |    | ginning |       |       |   | cartilage |           |
|        |    | 5 min   |       |       |   | damage,   |           |
|        |    | before  |       |       |   | bone      |           |
|        |    | react   |       |       |   | damage)   |           |
|        |    | ivation |       |       |   |           |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| Ant    | M  | SC CI   | 1.5   | Not   |   | Complete  | Van de    |
| igen-i | ou |         | mg/   | deter |   | p         | Loo et    |
| nduced | se |         | kg/hr | mined |   | revention | al.       |
| art    |    |         |       |       |   | of        | (1995)^9^ |
| hritis |    |         |       |       |   | su        |           |
|        |    |         |       |       |   | ppression |           |
|        |    |         |       |       |   | of        |           |
|        |    |         |       |       |   | pro       |           |
|        |    |         |       |       |   | teoglycan |           |
|        |    |         |       |       |   | synthesis |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| Immune | M  | SC CI   | 1.7   | 8     |   | Complete  | Van Lent  |
| com    | ou |         | mg/   | 0-90% |   | p         | et al.    |
| plex-i | se |         | kg/hr |       |   | revention | (         |
| nduced |    |         |       |       |   | of        | 1995)^42^ |
| art    |    |         |       |       |   | su        |           |
| hritis |    |         |       |       |   | ppression |           |
|        |    |         |       |       |   | of        |           |
|        |    |         |       |       |   | pro       |           |
|        |    |         |       |       |   | teoglycan |           |
|        |    |         |       |       |   | synthesis |           |
+--------+----+---------+-------+-------+---+-----------+-----------+
| Coll   | M  | SC CI   | 5     | 92%   |   | P         | Amgen,    |
| agen-i | ou | for     | mg/   |       |   | rotection | Inc.,     |
| nduced | se |         | kg/hr | 81%   |   | of        | data on   |
| art    |    | 7 days  |       |       |   | cartilage | file      |
| hritis |    | after   | 1     |       |   | metabolic | CIIM3^45^ |
|        |    | onset   | mg/   |       |   | integrity |           |
|        |    | of      | kg/hr |       |   |           |           |
|        |    | c       |       |       |   |           |           |
|        |    | linical |       |       |   |           |           |
|        |    | signs   |       |       |   |           |           |
+--------+----+---------+-------+-------+---+-----------+-----------+

\* Bone and cartilage effects are expressed as % inhibition; however,
measures tested vary between experiments and models as listed in the
table and may not be comparable from one model to another.\
SC CI = Continuous subcutaneous infusion

Figure 3‑2. Effects of Continuous Subcutaneous Infusion of Anakinra on
Ankle Swelling in Type II Collagen Arthritis in Female Lewis Rats

![](media/image2.wmf){width="5.585416666666666in"
height="3.3055555555555554in"}

Lewis rats were injected with bovine type II collagen in incomplete
Freund's adjuvant SC on days 0 and 7. Anakinra was administered by
continuous infusion for 7 days starting on the day of onset of clinical
signs of arthritis (day 13 to 15). Anakinra doses of 5, 1, and
0.2 mg/kg/hour resulted in a statistically significant reduction in paw
swelling analyzed as area under the curve (p \< 0.05, Student\'s
*t*‑test). Symbols represent the mean + standard error of the mean for
8 animals per group.^39^

CSEP = vehicle containing sodium citrate, sodium chloride, EDTA and
polysorbate-80.

In animal models of arthritis, the effects of anakinra on inhibition of
bone and cartilage destruction are similar, or better, than its effects
on inflammation (Figure 3-3).^39,40,43^ The bone protective effect of
anakinra is accompanied by a reduction in osteoclast numbers.^39,43^

Figure 3‑3. Anakinra Inhibits Inflammation as Well as Cartilage and Bone
Damage in\
Type II Collagen Arthritis in Female Lewis Rats

![](media/image3.jpeg){width="5.991666666666666in"
height="3.4458333333333333in"}

Lewis rats were injected with bovine type II collagen in incomplete
Freund's adjuvant SC on days 0 and 7. Anakinra was administered by
continuous infusion for 7 days starting on the day of onset of clinical
signs of arthritis (day 13 to 15). Anakinra doses of 5, 1, and 0.2
mg/kg/hour resulted in a statistically significant reduction in
histological scores for inflammation, pannus, cartilage and bone damage\
(\*p \< 0.05, Student\'s *t*‑test). Bars represent the mean +/‑ standard
error of the mean for 8 animals per group.^39^

### Effects of Anakinra Co-administered With Other Therapies

In clinical practice, co-administration of therapeutic agents has become
standard practice in the treatment of RA. The efficacy of
co-administering anakinra with other therapies has been evaluated in
animal models (see Table 3-4). Anakinra added to treatment with
MTX,^44,45^ or indomethacin^45^ results in added benefit in animal
models of arthritis. The efficacy of combining anakinra with anti-TNF
therapies has also been evaluated in animal models. In most models,
complete inhibition of inflammation can be achieved with anti-IL-1 or
anti-TNF treatment, whereas in others, such as adjuvant arthritis
induced by mycobacteria in Lewis rats, neither anti-IL-1 nor anti-TNF
treatment will completely inhibit disease. However, combined anti-IL-1
and anti-TNF treatment can result in additive^46^ or synergistic
effects.^38^

Table 3‑4. Co-administration of Anakinra With Other RA therapies

+--------+----+---------------------------+-------+----+------+------+
| **     | *  | **Treatment**             | *     | ** |      | *    |
| Animal | *S |                           | *Infl | Bo |      | *Ref |
| M      | pe |                           | ammat | ne |      | eren |
| odel** | ci |                           | ion** | a  |      | ce** |
|        | es |                           |       | nd |      |      |
|        | ** |                           | **%   | C  |      |      |
|        |    |                           | In    | ar |      |      |
|        |    |                           | hibit | ti |      |      |
|        |    |                           | ion** | la |      |      |
|        |    |                           |       | ge |      |      |
|        |    |                           |       | Ef |      |      |
|        |    |                           |       | fe |      |      |
|        |    |                           |       | ct |      |      |
|        |    |                           |       | s^ |      |      |
|        |    |                           |       | a^ |      |      |
|        |    |                           |       | ** |      |      |
+--------+----+---------------------------+-------+----+------+------+
| My     | R  | IL-1ra 1mg/kg/hr sc days  | 25%   | 2  | In   | Am   |
| cobact | at | 9-16 of study             |       | 2% | hibi | gen, |
| eria-i |    |                           | 21%   |    | tion | I    |
| nduced |    | Indomethacin 0.3 mg/kg po |       | 4% | of   | nc., |
| ad     |    | days 9-16 of study        |  68% |    | hi   | data |
| juvant |    |                           |       |   | stol | on   |
| art    |    | IL-1ra + Indomethacin     |       | 1  | ogic | file |
| hritis |    | Both                      |       | 8% | s    |      |
|        |    |                           |       |    | core | ADA  |
|        |    |                           |       |    | (b   | 65   |
|        |    |                           |       |    | one, | ^45^ |
|        |    |                           |       |    | eros |      |
|        |    |                           |       |    | ion) |      |
+--------+----+---------------------------+-------+----+------+------+
| Coll   | R  | IL-1ra 0.2 mg/kg/hr sc    | 30%   | -  | In   | Am   |
| agen-i | at | day 1-6 post onset        |       | 2% | hibi | gen, |
| nduced |    |                           | 49%   |    | tion | I    |
| art    |    | Indomethacin 0.3 mg/kg po |       | -  | of   | nc., |
| hritis |    | day 1-6 post onset        |  68% | 6% | hi   | data |
|        |    |                           |       |    | stol | on   |
|        |    | IL-1ra + Indomethacin     |       |   | ogic | file |
|        |    | Both                      |       | 4% | s    |      |
|        |    |                           |       |    | core | CILe |
|        |    |                           |       |    | (b   | w-28 |
|        |    |                           |       |    | one, | ^45^ |
|        |    |                           |       |    | eros |      |
|        |    |                           |       |    | ion, |      |
|        |    |                           |       |    | pan  |      |
|        |    |                           |       |    | nus, |      |
|        |    |                           |       |    | ca   |      |
|        |    |                           |       |    | rtil |      |
|        |    |                           |       |    | age) |      |
+--------+----+---------------------------+-------+----+------+------+
| My     | R  | IL-1ra 1 mg/kg/hr sc days | 51%   | 1  | In   | Am   |
| cobact | at | 9-16 of study             |       | 1% | hibi | gen, |
| eria-i |    |                           | 12%   |    | tion | I    |
| nduced |    | MTX 0.3 mg/kg days 9-16   |       | 4% | of   | nc., |
| ad     |    | of study                  |  88% |    | hi   | data |
| juvant |    |                           |       |   | stol | on   |
| art    |    | IL-1ra + MTX Both         |       | 3  | ogic | file |
| hritis |    |                           |       | 2% | s    |      |
|        |    |                           |       |    | core | AD   |
|        |    |                           |       |    | (b   | A-56 |
|        |    |                           |       |    | one, | ^45^ |
|        |    |                           |       |    | eros |      |
|        |    |                           |       |    | ion) |      |
+--------+----+---------------------------+-------+----+------+------+
| Li     | R  | IL-1ra 5 mg/kg/hr sc days | 6%    | 5  | In   | Ben  |
| poidal | at | 8-15 of study             |       | 3% | hibi | dele |
| a      |    |                           | 45%   |    | tion | et   |
| mine-i |    | MTX 75 μg/kg/day po days  |       | 5  | of   | al.  |
| nduced |    | 0-15 of study             |  78% | 8% | bone | (1   |
| ad     |    |                           |       |    | re   | 999) |
| juvant |    | IL-1ra + MTX Both         |       |   | sorp | ^44^ |
| art    |    |                           |       | 9  | tion |      |
| hritis |    |                           |       | 7% |      |      |
+--------+----+---------------------------+-------+----+------+------+
| My     | R  | IL-1ra 0.2 mg/kg/hr sc    | 13%   | -1 | In   | F    |
| cobact | at | days 9-16 of study        |       | 6% | hibi | eige |
| eria-i |    |                           | 23%   |    | tion | et   |
| nduced |    | PEG-sTNF-RI 0.25 mg/kg/hr |       | 2  | of   | al.  |
| ad     |    | sc days 9-16 of study     |  78% | 6% | bone | (2   |
| juvant |    |                           |       |    | min  | 000) |
| art    |    | IL-1ra + PEG-sTNF-RI^b^   |       |   | eral | ^38^ |
| hritis |    | Both                      |       | 6  | den  |      |
|        |    |                           |       | 4% | sity |      |
|        |    |                           |       |    | loss |      |
+--------+----+---------------------------+-------+----+------+------+
| Li     | R  | IL-1ra 100 mg/kg (HA) day | 14%   | 4  | In   | Ben  |
| poidal | at | 8-13 of study             |       | 3% | hibi | dele |
| a      |    |                           | 44%   |    | tion | et   |
| mine-i |    | PEG-sTNF-RI^b^ 3 mg/kg sc |       | 5  | of   | al.  |
| nduced |    | days 9, 11, 13 of study   |  56% | 6% | bone | (2   |
| ad     |    |                           |       |    | re   | 000) |
| juvant |    | IL-1ra +PEG-sTNF-RI^b^    |       |   | sorp | ^46^ |
| art    |    | Both                      |       | 10 | tion |      |
| hritis |    |                           |       | 0% |      |      |
+--------+----+---------------------------+-------+----+------+------+
| Coll   | R  | IL-1ra 20 mg/kg (HA )     | 11%   | 4% | In   | Ben  |
| agen-i | at | days 1-6 post onset       |       |    | hibi | dele |
| nduced |    |                           | 29%   | 2  | tion | et   |
| art    |    | PEG-sTNF-RI^b^ 0.3 mg/kg  |       | 1% | of   | al.  |
| hritis |    | day 1, 3, 5\              |  54% |    | hi   | (2   |
|        |    | IL-1ra + PEG-sTNF-RI^b^   |       |   | stol | 000) |
|        |    | Both                      |       | 6  | ogic | ^46^ |
|        |    |                           |       | 1% | sc   |      |
|        |    |                           |       |    | ores |      |
|        |    |                           |       |    | (sy  |      |
|        |    |                           |       |    | novi |      |
|        |    |                           |       |    | tis, |      |
|        |    |                           |       |    | c    |      |
|        |    |                           |       |    | arti |      |
|        |    |                           |       |    | lage |      |
|        |    |                           |       |    | dam  |      |
|        |    |                           |       |    | age, |      |
|        |    |                           |       |    | bone |      |
|        |    |                           |       |    | dam  |      |
|        |    |                           |       |    | age) |      |
+--------+----+---------------------------+-------+----+------+------+

^a^ Bone and cartilage effects are expressed as % inhibition; however,
parameters tested vary between experiments and models as listed in the
table and may not be comparable from one model to another.

^b^ PEG sTNF-RI -- PEGylated recombinant soluble TNF-Receptor I (Amgen,
Inc.)

## Nonclinical Pharmacokinetics of Anakinra

The pharmacokinetic profile of anakinra was examined in rats, rabbits,
and monkeys. Anakinra disappeared rapidly from the plasma after either
IV or SC bolus doses in all 3 species; the terminal half-life values
after SC bolus administration were 0.89, 1.18, and 3.03 hours for rats,
rabbits, and monkeys, respectively. The systemic exposure of anakinra
increased proportionally with dose. Anakinra appeared to be cleared by
glomerular filtration in the kidney, followed by metabolism in the
kidney tubules. No apparent gender differences in the pharmacokinetics
of anakinra were observed. No apparent changes in anakinra
pharmacokinetics could be determined when either MTX or PEG sTNF-RI was
administered concurrently.

## Toxicology

Anakinra is similar, but not identical, to the analogous receptor
antagonist proteins of other species, and has been shown to be
biologically active in a wide variety of species, including those used
in the toxicity studies. Subchronic and chronic toxicity studies were
conducted in rats and subchronic studies were conducted in nonhuman
primates. Because the principal biological action of anakinra is to
antagonize the effects of IL-1 and because anakinra does not possess
intrinsic agonist activity, no exaggerated pharmacologic effects from
high doses of anakinra were expected, nor were any seen. Anakinra is a
foreign protein in the species used for preclinical safety assessment;
as such, anti-anakinra antibodies were an anticipated finding.
Non-neutralizing anti-anakinra antibodies were detectable in both rats
and monkeys.

The following is a brief summary of completed studies.

-   In non-human primates, the no observed effect level (NOEL) based on
    systemic toxicity effects is considered to be 100 mg/kg/day; based
    on local injection site effects the NOEL is less than 10 mg/kg/day.

-   Twice-daily SC administration of anakinra (BID) for 6 months to rats
    at total doses of 2, 20, and 200 mg/kg/day produced local injection
    site inflammation at all dosages, the incidence and severity of
    which increased with dose. Systemic toxicity at 200 mg/kg/day was
    limited to the kidney with increased kidney weights, proteinuria,
    and chronic progressive nephropathy being the principal findings
    after 6 months of dosing. Chronic progressive nephropathy is a
    background disease in aging rats,^47-49^ with higher incidence in
    males,^50^ and is known to be influenced by protein levels.^51-54^
    Kidney toxicity was not evident at the 1-month interim necropsy or
    after the 1-month recovery period.

-   No adverse effects of anakinra were noted in any reproductive
    toxicity or teratology studies in rats and rabbits, conducted at
    dosages up to 200 mg/kg/day.

-   No evidence of genotoxicity was found in mutagenicity assays.

-   Neither pre-neoplastic lesions nor tumors related to anakinra
    treatment were observed in a 6-month study of anakinra in rats at
    doses up to 200 mg/kg/day. Thus, there is no evidence of anakinra
    being involved in direct tumor production.

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-   In preclinical toxicology studies in rats and monkeys, no evidence
    of immunosuppression was seen. Additionally, anakinra had no effect
    on specific immune function tests, such as antibody formation to
    keyhole limpet hemocyanin or sheep red blood cells, cytolytic T
    lymphocyte response in mice or NK cell activity in rats and monkeys.

-   Published studies, including studies on IL-1 knockout and IL-1Ra
    over-expressing mice ^22,55-60^ do not reveal a clear or consistent
    picture on the role of IL-1 inhibition in compromising host
    resistance to bacterial infection. For example, IL-1β or IL-1R
    knock-out mice showed no increased susceptibility to infectious
    challenges, while IL-1Ra over-expressing mice were more susceptible.

-   In acute host resistance rat models infected with *E coli*, *S
    aureus*, and *L monocytogenes*, anakinra did not increase mortality
    following these infections and its effect on host resistance (based
    on CFU in blood, liver, or spleen) was slight to non-existent.
    Therefore, anakinra does not appear to greatly impair host
    resistance mechanisms.

-   The effects of combined administration of anakinra with MTX or with
    cytokine inhibitors were investigated:

    -   Coadministration of anakinra and MTX (in rats) or PEG sTNF-RI
        (in rats and monkeys), did not show any toxicity or
        pharmacokinetic interactions between the two agents.

    -   There was no evidence in monkeys and rats of detrimental
        anakinra interaction with the cytokine inhibitors, etanercept
        and PEG sTNF-RI in blood cell counts, body and lymphoid organ
        (spleen, thymus) weights, lymphoid organ cellularity, lymphoid
        organ viability, NK cell function, immune cell phenotype, and
        antibody response to keyhole limpet hemocyanin or the anti-sheep
        red blood antibody-forming cell (AFC) assay.

## Summary of Nonclinical Studies

In conclusion, preclinical studies demonstrate that anakinra has well
characterized in vitro and in vivo profiles and is a selective
antagonist of IL-1. Notable inhibition of inflammation, bone
destruction, and cartilage degeneration have been observed in several
animal models of arthritis following treatment with anakinra. The
nonclinical pharmacokinetic studies demonstrate that anakinra appears to
be cleared by glomerular filtration in the kidney, followed by
subsequent metabolism in the kidney tubules.

The results of the nonclinical toxicity studies evaluating doses up to
200 mg/kg/day for 6 months demonstrate that the effects of anakinra are
consistent with the clinical safety profile, with local injection site
effects as the primary safety observation, and little to no systemic
toxicity. Additionally, in toxicology studies of anakinra in combination
with anti-TNF therapies there was no evidence of detrimental interaction
of anakinra with the TNF inhibitors in cellular function assays of
immune competence.

# Clinical Data 

## Introduction

Clinical data to support the RA indication are discussed in the
following sections. A total of 19 clinical trials (including extension
trials and studies in healthy volunteers) have been conducted. A total
of 2606 RA subjects have been treated with anakinra, of which 2332 were
from the 5 randomized, placebo-controlled studies and their extensions.
A brief overview of data from clinical pharmacology trials is provided
in Section 4.2, followed by a detailed description of the 5 randomized,
placebo-controlled RA trials, including study design and baseline
characteristics (Section 4.3). Efficacy and safety data from these 5
studies are discussed in Section 4.4 and Section 4.5, respectively.

Anakinra has also been studied in other indications including sepsis,
graft versus host disease, and asthma. While anakinra has not been
marketed in these indications, the safety data in settings such as
sepsis, where the immune system is drastically compromised, provide
additional assurance that anakinra has an acceptable safety profile.
Safety data from sepsis trials are summarized in Section 4.5.6.6.

## Human Pharmacokinetics and Bioavailability

Anakinra was well absorbed after SC administration in healthy subjects
(N = 11) with an absolute bioavailability of 95%. In subjects with RA,
maximum plasma concentrations of anakinra occurred at 3 to 7 hours after
SC administration of anakinra at clinically-relevant doses (1 to 2
mg/kg; N = 18). Since plasma clearance values of anakinra after SC
administration are independent of dose (range = 84 to 124 mL/min), the
systemic exposure of anakinra increases in a proportional manner with
higher doses. The terminal half-life ranged from 4 to 6 hours. No
unexpected accumulation of anakinra was observed after daily SC doses
for up to 24 weeks.

After single IV administration of anakinra (1 to 2 mg/kg) in healthy
subjects (N = 21), anakinra disappeared rapidly from the plasma with a
terminal half-life of approximately 2 to 3 hours. The shorter half-life
after IV administration than after SC administration suggests that the
rate of anakinra clearance from plasma was limited by the absorption
process. The initial volume of distribution approximated the plasma
volume; at steady state, the volume of distribution was similar in
magnitude to the extracellular water volume. The plasma clearance values
of anakinra were independent of dose and ranged from 133 to 170 mL/min,
which were moderately higher than the estimate of the glomerular
filtration rate (estimated creatinine clearance range = 99 to
149 mL/min).

Animal data demonstrated that the kidney was the major organ responsible
for elimination of anakinra (80% in rats). Since in humans very little
anakinra appeared in the urine (\< 10% of the dose administered), it was
postulated that anakinra was filtered at the glomeruli and reabsorbed in
the proximal tubules wherein it was metabolized.

Subjects with end stage renal disease on dialysis (N = 20) had a
substantially lower plasma clearance of approximately 18 mL/min and a
longer terminal half-life (approximately 7 hours) than healthy subjects
after IV administration. Plasma clearance of anakinra was also lower in
subjects with hepatic dysfunction (Child classification B, N = 12,
CL = 95 mL/min) than in healthy subjects after IV administration; the
decrease in plasma clearance correlated with a slight decrease in
estimates of creatinine clearance in this population.

The effect of baseline covariates on the pharmacokinetics of anakinra
was studied by population pharmacokinetic analysis of sparse data (1 to
5 data points per subject) obtained from 341 subjects with active RA
over a 24-week treatment period in the Monotherapy Study (0560). Results
showed that plasma clearance was reduced in subjects with lower
estimates of creatinine clearance and lower body weight. Mean estimated
plasma clearance after SC bolus administration was approximately 12%
lower in women (N = 262) than in men (N = 79) and approximately 9% lower
in subjects ≥ 65 years (N = 79) than in subjects \< 65 years (N = 262);
however, these differences could be explained by the differences in the
estimated creatinine clearance and measured body weight.

In conclusion, anakinra reached maximum concentration at 3 to 7 hours
after SC administration, and was eliminated from the plasma with a
terminal half-life of 4 to 6 hours. Systemic exposure of anakinra
increased proportionally to dose. Both creatinine clearance and body
weight were predictors of plasma clearance of anakinra; plasma clearance
was higher in subjects with higher creatinine clearance and body weight.

## Placebo-controlled Clinical Trials in Rheumatoid Arthritis

Five randomized, placebo-controlled trials, representing the clinical
experience of over 2900 subjects support the positive risk/benefit
profile of anakinra for the treatment of RA, see Table 4-5. In
particular, the Confirmatory Efficacy Study (990145) prospectively
confirmed the efficacy of anakinra in reducing the signs and symptoms of
RA at the proposed dose of 100 mg/day. In addition, the Safety Study
(990757) with 1399 subjects, together with safety data from 501 subjects
in the Confirmatory Efficacy Study (990145), established the safety of
anakinra at the proposed dose of 100 mg/day.

The study designs for the 5 randomized, placebo-controlled trials are
discussed in Section 4.3.1, followed by a review of the baseline
characteristics of the subjects enrolled in each trial (Section 4.3.2).
Efficacy and safety data from these studies are discussed in Section 4.4
and Section 4.5, respectively.

Table 4‑5. Placebo-controlled Trials in Rheumatoid Arthritis

  ----------- ------------------------------ ------------------------- ------------
  **Study**   **Description**                **Daily Doses of          **N**
                                             Anakinra**                

  0560        Monotherapy Study              0, 30, 75, 150 mg         472

  960182      Low Dose Monotherapy Study     0, 2.5, 10, 30 mg         141

  960180      MTX Combination Study          0, 0.04, 0.1, 0.4, 1.0,   419
                                             2.0 mg/kg                 

  990145      Confirmatory Efficacy Study    0, 100 mg                 501

  990757      Safety Study                   0, 100 mg                 1399

                                             ***Total***               ***2932***
  ----------- ------------------------------ ------------------------- ------------

N = Number of subjects who received at least 1 dose of study drug

### Study Designs: Placebo-controlled Trials

The key design features for each of the 5 trials are summarized in
Table 4-6. All studies were randomized, double-blind, and
placebo-controlled for a treatment period of up to 24 weeks, except for
the Low Dose Monotherapy Study, 960182, which was a smaller pilot study
of 12-weeks duration. The Monotherapy Study (0560) and Low Dose
Monotherapy Study (960182) assessed the safety and efficacy of anakinra
as a monotherapy. Subjects were not permitted to be on any concurrent
DMARD therapy, and the subjects participating were representative of
both a DMARD failure and DMARD naïve RA population. The MTX Combination
Study (960180) and the Confirmatory Efficacy Study (990145) examined the
safety and efficacy of anakinra in combination with background
methotrexate (MTX). The Safety Study (990757) investigated the safety of
anakinra in a large (N = 1399; 4:1 randomization ratio anakinra:placebo)
RA population that included subjects with varying disease severity. The
study also had minimal restrictions regarding the use of concomitant RA
therapies. Eligibility criteria included subjects who were DMARD naïve,
DMARD failures, or were receiving concurrent single or multiple DMARD
therapies (DMARD "all comers" trial). The following sections describe
the study design for each of these 5 trials in greater detail.

#### Monotherapy Study (0560)

The Monotherapy Study (0560) enrolled 473 subjects (472 treated) in 11
European countries, and was designed to evaluate the efficacy of
anakinra as a monotherapy compared with placebo. The study was initiated
in May 1994 and completed enrollment in November 1995. Subjects with
early, active RA who had failed no more than 3 previous DMARDs or who
were DMARD-naïve were enrolled into the study and randomized (using an
equal allocation ratio) to receive either placebo or 1 of 3 doses of
anakinra (30, 75, or 150 mg) administered as daily SC injections for a
period of 24 weeks. Evidence of active RA required at least 10 swollen
joints capable of response at screening and at least 3 of the following
4 criteria: 1) [\>]{.underline} 10 tender joints, 2) investigator
assessment of severe or very severe disease activity, 3) subject
assessment of severe or very severe disease activity, or 4) C-reactive
protein (CRP) levels \> 1.5 mg/dL. Subjects were not permitted to be on
any concurrent DMARD therapy while participating in the trial.

The primary endpoint was the proportion of subjects exhibiting at least
a 20% improvement from baseline in the American College of Rheumatology
(ACR) composite score at week 24 (ACR~20~). An important secondary
endpoint was the change from baseline at week 24 in the Larsen score.
Hand/wrist radiographs were taken at baseline and at 24 weeks and
assessed joint destruction as measured by Larsen score. Although the
Larsen score was the prespecified radiographic endpoint in the 0560
protocol, these same radiographs were later re-scored using a modified
Sharp scoring system which is reported to be a more sensitive measure of
joint destruction.^61,62^ The results for both the prespecified Larsen
score and the modified Sharp score are provided (Section 4.4.2).

*Table 4‑6. Design Overview of Randomized Placebo-controlled Trials in
RA*

+----+-----------+--------+-----+-----+------+---+-----------+------+
| S  | Study     | C      | Sta | Pr  | Sub  | N | Doses and | D    |
| tu | Design    | ountry | tus | ima | ject |   | Route     | urat |
| dy |           |        |     | ry\ | Po   |   |           | ion\ |
|    |           |        |     | Obj | pula |   |           | of   |
|    |           |        |     | ect | tion |   |           | Do   |
|    |           |        |     | ive |      |   |           | sing |
|    |           |        |     | (s) |      |   |           |      |
+====+===========+========+=====+=====+======+===+===========+======+
| 05 | Doub      | Europe | Co  | Eff | Ac   | 4 | Fixed     | 24   |
| 60 | le-blind, |        | mpl | ica | tive | 7 | Dosing    | w    |
|    | ra        |        | ete | cy\ | RA;  | 2 |           | eeks |
|    | ndomized, |        |     | Saf |      |   | 30, 75,   |      |
|    | placebo-c |        |     | ety | DMAR |   | or 150    |      |
|    | ontrolled |        |     |     | D-na |   | mg/day\   |      |
|    |           |        |     |     | ïve\ |   | SC        |      |
|    |           |        |     |     | D    |   |           |      |
|    |           |        |     |     | MARD |   |           |      |
|    |           |        |     |     | Fail |   |           |      |
|    |           |        |     |     | ures |   |           |      |
+----+-----------+--------+-----+-----+------+---+-----------+------+
| 96 | Doub      | Europe | Co  | Eff | Ac   | 1 | Fixed     | 12   |
| 01 | le-blind, |        | mpl | ica | tive | 4 | Dosing    | w    |
| 82 | ra        |        | ete | cy\ | RA;  | 1 |           | eeks |
|    | ndomized, |        |     | Saf |      |   | 2.5, 10,  |      |
|    | placebo-c |        |     | ety | DMAR |   | or 30     |      |
|    | ontrolled |        |     |     | D-na |   | mg/day\   |      |
|    |           |        |     |     | ïve\ |   | SC        |      |
|    |           |        |     |     | D    |   |           |      |
|    |           |        |     |     | MARD |   |           |      |
|    |           |        |     |     | Fail |   |           |      |
|    |           |        |     |     | ures |   |           |      |
+----+-----------+--------+-----+-----+------+---+-----------+------+
| 96 | Doub      | United | Co  | Eff | Ac   | 4 | Wei       | 1    |
| 01 | le-blind, | S      | mpl | ica | tive | 1 | ght-Based | 2-24 |
| 80 | ra        | tates, | ete | cy\ | RA;\ | 9 | Dosing    | w    |
|    | ndomized, | C      |     | Saf | On   |   |           | eeks |
|    | placebo-c | anada, |     | ety | MTX  |   | 0.04,     |      |
|    | ontrolled | and    |     |     |      |   | 0.1, 0.4, |      |
|    |           | Aus    |     |     |      |   | 1.0, or   |      |
|    |           | tralia |     |     |      |   | 2.0       |      |
|    |           |        |     |     |      |   | m         |      |
|    |           |        |     |     |      |   | g/kg/day\ |      |
|    |           |        |     |     |      |   | SC        |      |
+----+-----------+--------+-----+-----+------+---+-----------+------+
| 9  | Doub      | United | 6   | Eff | Ac   | 5 | Fixed     | 24   |
| 90 | le-blind, | S      | -mo | ica | tive | 0 | Dosing    | week |
| 14 | ra        | tates, | nth | cy\ | RA;\ | 1 |           | s^c^ |
| 5^ | ndomized, | C      | Si  | Saf | On   | ^ | 100       |      |
| a^ | p         | anada, | gns | ety | MTX  | b | mg/day\   |      |
|    | lacebo-co | and    | and |     |      | ^ | SC        |      |
|    | ntrolled\ | Aus    | Sy  |     |      |   |           |      |
|    | (O        | tralia | mpt |     |      |   |           |      |
|    | pen-label |        | oms |     |      |   |           |      |
|    | after     |        | An  |     |      |   |           |      |
|    | 1         |        | aly |     |      |   |           |      |
|    | 2 months) |        | sis |     |      |   |           |      |
|    |           |        | Co  |     |      |   |           |      |
|    |           |        | mpl |     |      |   |           |      |
|    |           |        | ete |     |      |   |           |      |
|    |           |        | ^a^ |     |      |   |           |      |
+----+-----------+--------+-----+-----+------+---+-----------+------+
| 9  | Doub      | United | 6   | Saf | Ac   | 1 | Fixed     | 24   |
| 90 | le-blind, | S      | -mo | ety | tive | 3 | Dosing    | week |
| 75 | ra        | tates, | nth |     | RA;\ | 9 |           | s^c^ |
| 7^ | ndomized, |        | An  |     | DMAR | 9 | 100       |      |
| d^ | p         | E      | aly |     | D-na |   | mg/day\   |      |
|    | lacebo-co | urope, | sis |     | ïve\ |   | SC        |      |
|    | ntrolled\ |        |     |     | D    |   |           |      |
|    | (O        | C      | Co  |     | MARD |   |           |      |
|    | pen-label | anada, | mpl |     | Fail |   |           |      |
|    | after     | and    | ete |     | ures |   |           |      |
|    | 6 months) | Aus    | ^d^ |     |      |   |           |      |
|    |           | tralia |     |     | Co   |   |           |      |
|    |           |        |     |     | ncur |   |           |      |
|    |           |        |     |     | rent |   |           |      |
|    |           |        |     |     | DM   |   |           |      |
|    |           |        |     |     | ARDs |   |           |      |
+----+-----------+--------+-----+-----+------+---+-----------+------+

N, number of subjects treated; SC, subcutaneous.

^a^ The trial continues to be double-blind and placebo-controlled for
assessment of the 52-week radiographic endpoint.

^b^ Number of subjects randomized as of the 18 May 2000 cut-off date and
received at least 1 dose of study drug for the analysis of signs and
symptoms data.

^c^ 24-week period included in this analysis.

^d^ First 24-weeks is double-blind, placebo-controlled. After 24 weeks,
the trial becomes open-label for an additional 2½ years.

The statistical analysis plan prespecified the primary efficacy subset
to be the Modified Intent-to-Treat (M-ITT) subset. The M-ITT subset
included subjects who received at least 1 dose of study drug as well as
having at least 1 postbaseline measurement for the particular endpoint
evaluated. The analysis plan also defined the last observation carried
forward (LOCF) technique as the method for imputing missing data.
Additional analyses for the ACR composite score evaluated the
Intent-to-Treat (ITT) subset and included all subjects receiving at
least 1 dose of study drug. For these additional analyses a
non-responder (treatment failure) imputation method was employed for
missing data. All subjects were followed for safety assessments.

#### Low Dose Monotherapy Study (960182)

The Low Dose Monotherapy Study (960182) was a 12-week randomized,
double-blind, placebo-controlled pilot study conducted in 15 centers in
6 European countries. The study was designed to explore the lower
anakinra dose range in a monotherapy setting using entry criteria
similar to those in study 0560. As in the Monotherapy Study (0560),
subjects were not permitted to receive concurrent DMARD therapy. The
study was initiated in February 1997 and concluded in September 1997. A
total of 141 subjects were randomized to receive either placebo or 1 of
3 anakinra doses: 2.5, 10, or 30 mg/day. The study employed an unequal
allocation ratio randomizing a greater number of subjects to the 2.5 and
10 mg anakinra groups (N \~ 40 per group) relative to either the placebo
or 30 mg groups (N \~ 25 per group) in order to gain more experience at
these 2 new anakinra doses since the 30 mg had been previously studied
in the Monotherapy Study (0560).

The primary endpoint was the proportion of subjects exhibiting at least
a 20% improvement from baseline in the American College of Rheumatology
(ACR) composite score at week 12 (ACR~20~). These data were analyzed
using the Intent-to-Treat (ITT) subset which included all subjects
receiving at least 1 dose of study drug with a non-responder (treatment
failure) imputation method. All subjects were followed for safety
assessments.

#### MTX Combination Study (960180)

The therapeutic benefit of anakinra in combination with MTX was examined
in the MTX Combination Study (960180). This study, which began in
December 1996 and was completed in March 1999, was conducted at sites in
United States, Canada, and Australia. The study was designed to evaluate
the efficacy of anakinra in the reduction of signs and symptoms of RA
across a range of doses using a mg/kg dosing scheme and enrolled
subjects with RA who showed signs of active RA despite treatment with
stable doses of MTX (15 to 25 mg/wk). Eligible subjects were required to
have active RA as evidenced by at least 6 swollen joints, and 2 of the
following 3 criteria: 1) ≥ 9 tender/painful joints, 2) morning stiffness
≥ 45 minutes duration, or 3) CRP ≥ 1.5 mg/dL.

A total of 419 subjects were randomized to receive daily SC injections
of either placebo or 1 of 5 doses of anakinra (0.04, 0.10, 0.40, 1.0 or
2.0 mg/kg) for up to 24 weeks. All subjects were required to be on
stable doses of MTX throughout the study period.

The primary efficacy endpoint was the proportion of subjects achieving
an ACR~20~ response at week 12. The primary analysis was a single test
of dose-response examining the ACR~20~ response rates at week 12 across
the 6 randomized treatment groups. Due to the directional nature of the
analysis, increasing ACR~20~ response rates with increasing dose, an
alpha level of 0.025 was used to assess statistical significance. If
this overall omnibus test for dose-response was significant, individual
pairwise comparisons of each anakinra dose group to placebo were to be
conducted. This primary analysis was conducted using the ITT subset and
a non-responder imputation algorithm for missing data. Secondary
endpoints included the ACR~20~, ACR~50~, and ACR~70~ responses at week
24. In addition, the sustained ACR~20~ response rate, defined as an
achievement of an ACR~20~ response for a minimum of 4 of 6 monthly
measurements (with at least one response at the week 12 or 24 time
point) was also examined. This latter measurement provides an assessment
of durability of response across the entire treatment period. All
subjects were followed for safety assessments.

The original 960180 protocol was designed as a 12-week study with 3
anakinra doses (0.1, 0.4, and 2.0 mg/kg/day). In April 1997, prior to
any blind break, an amendment increasing the study duration from 12 to
24 weeks and adding incremental visits at weeks 16, 20, and 24 was
initiated. The amendment also expanded the number of anakinra dose
groups, adding 2 new doses of 0.04 and 1.0 mg/kg/day. In addition, the
sample size for the 12-week assessment was increased from 30 subjects
per group to 70. A total of 314 additional subjects were randomized to
receive either placebo or 1 of the 5 anakinra treatment groups after
this amendment became effective.

#### Confirmatory Efficacy Study (990145)

The Confirmatory Efficacy Study 990145 is a randomized, double-blind,
placebo-controlled trial conducted in the United States, Canada, and
Australia. A total of 906 subjects on stable doses of background MTX (10
to 25 mg/wk) were randomized to receive either placebo or 100 mg/day of
anakinra using a 1:1 allocation ratio. For the first 24 weeks, subjects
were assessed every 4 weeks for the signs and symptoms of RA using the
ACR composite score. Safety was to be assessed at each visit. Although
originally designed and sized to evaluate the 52-week effects of
anakinra on the prevention of structural damage (modified Sharp score),
the 24-week signs and symptoms data for the first 501 subjects receiving
study drug were evaluated to provide additional data confirming the
efficacy of anakinra with respect to the signs and symptoms of RA. The
52-week radiographic assessment of disease progression, the study's
primary efficacy endpoint, remains blinded and will not be analyzed
until all subjects have completed their 52-week double-blind treatment
period. Subjects completing the 52-week double-blind portion of the
study may continue on open-label anakinra treatment for an additional 2
years. The study design is illustrated in\
Figure 4-1.

Figure 4‑4. Schema: Confirmatory Efficacy Study (990145)

![](media/image5.wmf){width="5.999305555555556in"
height="4.375694444444444in"}

Eligibility criteria included radiographic evidence of at least 1 bone
erosion in the hands/wrists or feet. Prior to randomization subjects
were also required to have a minimum of 6 swollen joints and 9
tender/painful joints and 1 of the following:\
CRP ≥ 1.5 mg/dL (15.0 mg/L), or erythrocyte sedimentation rate (ESR) ≥
28 mm/hr.

The higher frequency of injection-site reactions (ISRs) with SC
administration of anakinra relative to placebo seen in previous clinical
studies of anakinra suggested there may be the potential for unblinding
study assessors, and possibly introduce bias in their evaluation of
signs and symptoms endpoints. In an attempt to minimize such potential
bias, the 990145 protocol mandated that steps be taken to cover
subjects' injection sites with clothing during assessments of signs and
symptoms. Additionally, independent assessors blinded to all other
protocol-specified assessments were to be used for the evaluation of
swollen and tender/painful joints. Further, postbaseline CRP and ESR
values for individual subjects were kept blinded to Amgen and study site
personnel, as anakinra is known to affect these 2 acute phase reactants.
Sensitivity analyses to be discussed in the results section suggest that
the potential of unblinding due to ISRs did not influence the study's
overall conclusions, see Section 4.4.1.4.

####### On-Study Medications {#on-study-medications .FlushLeftBold .unnumbered}

In cases of RA flare, NSAIDs or oral corticosteroids could be added or
the dose could be temporarily increased postbaseline, with return to the
maintenance (baseline) dose upon resolution of the flare. Investigators
could also prescribe any other concomitant medications or treatments
necessary for supportive care during the 52-week double-blind portion of
the study except for the following: other investigational agents,
DMARDs, azathioprine, chronic minocycline, cyclophosphamide,
cyclosporine, etanercept, gold, hydroxychloroquine, infliximab,
leflunomide, mycophenolate mofetil, sulfasalazine, and tacrolimus.
Tetracycline could only be used for up to 10 days to treat infection.

In addition to the above medications, this study incorporated the use of
a special subject status designation, Lack of Efficacy (LOE), with the
objective of retaining subjects in the study for evaluation of the
radiographic endpoint when they might otherwise withdraw from the study
due to a flare in signs and symptoms of RA. LOE assessments were
conducted using a pre-defined algorithm, which maintained the study
blind regarding randomized treatment assignments. Declaration of LOE on
or after week 16 allowed subjects to receive treatment with
protocol-specified agents that could alleviate the signs and symptoms of
RA with minimal effects on underlying structural damage (see Appendix
4-1).

For the assessment of the signs and symptoms endpoint, subjects whose
dose of DMARDs or corticosteroids was increased from baseline for *any
reason*, including LOE, were defined as non-responders in the analysis
of the ACR composite score. The evaluation of the 24-week signs and
symptoms data also included sensitivity analyses to evaluate the impact
of on-study medication changes on the study's primary conclusion (see
Section 4.4.1.4).

####### Signs and Symptoms Endpoints {#signs-and-symptoms-endpoints .FlushLeftBold .unnumbered}

The primary efficacy endpoint for the assessment of signs and symptoms
was the proportion of subjects exhibiting ≥ 20% improvement from
baseline in the ACR composite score (ACR~20~) at week 24.

Secondary endpoints included:

-   The proportion of subjects achieving a sustained ACR~20~ response
    defined as an ACR~20~ response for a minimum of 4 of 6 monthly
    measurements, with at least one response being at week 12 or week
    24,

-   ACR~50~ and ACR~70~ responses at week 24, and

-   The change from baseline at week 24 for each of the individual ACR
    components.

####### Safety Evaluations {#safety-evaluations .FlushLeftBold .unnumbered}

Safety endpoints included treatment-emergent adverse events and serious
adverse events during the first 24 weeks of treatment. A
treatment-emergent adverse event was any clinical abnormality reported
by the subject or noted by the investigator that appeared or worsened
during the study, regardless of whether the investigator considered the
event related to study medication. Serious adverse events were any
events that suggested a significant hazard or side effect, regardless of
the investigator's or sponsor's opinion on the relationship to study
medication. These included, but were not limited to, events at any dose
that were fatal, life threatening (placed the subject at immediate risk
of death), required in-subject hospitalization or prolongation of an
existing hospitalization, were a persistent or significant
disability/incapacity, or were a congenital abnormality/birth defect.
Adverse events of an infectious nature were designated as such by the
principal investigator.

####### Statistical Methods {#statistical-methods .FlushLeftBold .unnumbered}

The statistical methodology employed for the analysis of signs and
symptoms including the declaration of study endpoints, sample size,
evaluable subsets, and statistical methods, was prospectively detailed
in the statistical analysis plan and discussed with the Agency prior to
any blind break. The sample size and analytic methods are briefly
outlined below.

-   **Sample Size Determination**

A sample size of approximately 500 subjects (250 per group) was
prespecified as the number of subjects required for a complete and
sufficient test of the primary hypothesis confirming the superiority of
anakinra plus MTX versus placebo plus MTX in the reduction of signs and
symptoms. Given a 2-tailed alpha level of 0.05 and using an uncorrected
chi-square test as an approximation to the prespecified logistic
regression analysis, the analysis of the ACR~20~ response rates at week
24 had 90% power to detect a delta of 13% or more between the anakinra
and placebo, 33% versus 20%, respectively.

The analysis for signs and symptoms was prespecified to be conducted at
the full 0.05 alpha level yielding a definitive assessment of signs and
symptoms. As such, there was no adjustment, or differential alpha
spending, incorporated into the sample size determination or analytic
methodology. In addition, there will be no adjustment to the alpha level
used to assess the radiographic endpoint at the study's conclusion
since:

-   the radiographic endpoint (baseline change at week 52 in the
    modified Sharp Total Score) is not included in the 24-week analysis,
    and all data associated with the Sharp score remain blinded, and

-   the radiographic disease progression claim and the signs and
    symptoms claim are based on different endpoints.

To protect the integrity of the 52-week radiographic endpoint,
procedures were implemented during the analysis and reporting of the
signs and symptoms data for this study. As prespecified, for the
purposes of conducting the analyses limited Amgen personnel were
unblinded to the individual subject treatment assignments. The only data
displayed by treatment group are aggregate (summary) statistical data.
The randomized treatment assignments for individual subjects are not
provided in any data presentations or narratives. Additionally, results
that may inadvertently unblind individual treatment assignments (eg, a
maximum age associated with a treatment group and easily identified to a
particular subject) have been withheld from all data presentations.

-   **Evaluable Subset for Efficacy**

All subjects who were randomized on or before 18 May 2000 and received
≥ 1 dose of study drug were included in all analyses of efficacy for the
assessment of signs and symptoms. Subjects were analyzed according to
their randomized treatment group regardless of the actual treatment
received. This subset of subjects is referred to as the Intent-to-Treat
(ITT) subset.

-   **Missing ACR Composite Scores: Non-Responder Imputation**

If a subject's ACR composite score could not be evaluated at a
particular time point because of missing data or incomplete assessments,
this subject was considered a non-responder (treatment failure) at that
time point. In addition, if a subject's dose of DMARDs or
corticosteroids was increased from baseline for *any reason*, the
subject was considered a non-responder after the first occurrence of the
increase in dose.

-   **Primary Analysis for the ACR~20~**

The prespecified primary analysis for the ACR~20~ response rate at week
24 was a logistic regression model adjusted for center. All subjects in
the evaluable ITT subset were included in the analysis. Subjects with
non-evaluable ACR~20~ responses at week 24 due to missing data or
increase in DMARDs or corticosteroids were considered non-responders.

#### Safety Study (990757)

The Safety Study (990757) is a 24 week randomized, double-blind,
placebo-controlled trial with a 2.5 year open-label phase for subjects
completing the 24-week double-blind portion. The primary objective and
design of this study was to assess the safety of anakinra in a large RA
population receiving a variety of concomitant RA medications, and with
pre-existing co-morbid conditions including a variety of DMARD
therapies. The study's primary endpoint was the subject incidence of
adverse events, including deaths, serious adverse events,
discontinuations due to adverse events, and infections. The study is
being conducted in the United States, Canada, Europe, and Australia.
Eligible subjects were randomized to receive either 100 mg/day of
anakinra or placebo using a 4:1 allocation ratio. There were minimal
exclusionary criteria regarding background DMARDs; however, subjects who
were being treated with DMARDs must have been receiving stable doses for
a minimum of 2 months before randomization. Evidence of active RA
required the presence of ≥ 3 swollen and ≥ 3 tender/painful joints or
morning stiffness of at least 45 minutes duration.

The study design (Figure 4-5) included a concurrent placebo group during
the first 6 months for comparison of the incidence of unexpected serious
adverse events (eg, opportunistic infections) with those in the anakinra
group during the same time interval. The safety data reported represent
the results of the double-blind, placebo-controlled portion of the
study. The open-label portion of the study is still in-progress.

Figure 4‑5. Schema: Safety Study (990757)

![](media/image6.wmf){width="5.998611111111111in"
height="3.122916666666667in"}^a^ Standard therapy was defined as the
medications and treatments the subject was receiving at screening.

Day 1 = first day study drug was administered. Study drug was to be
given within 4 days after randomization.

Eligible subjects were randomized to anakinra or placebo treatment in a
4:1 allocation ratio.

With minimal restrictions regarding the use of concomitant RA therapies,
the Safety Study (990757) was designed to provide safety data on the use
of anakinra in combination with a variety of background RA medications.
To achieve this objective, investigators were permitted to change the
dose of medications, including NSAIDs, corticosteroids, or DMARDs to
provide supportive care during the conduct of the study. Additionally,
any medication taken regularly before entry into the study could be
continued throughout the study with the exception of those prohibited by
the exclusion criteria and the proscribed medications such as
mycophenolate mofetil (CellCept^®^), tacrolimus (FK506, Prograf^®^),
cyclophosphamide (Cytoxan^®^), etanercept (Enbrel), sirolimus
(Rapamune^®^), infliximab (Remicade), PROSORBA^®^ Column, cyclosporine,
Zenapax (daclizumab), and Simulect (basiliximab).

### Subject Disposition and Baseline Characteristics

Overall withdrawal patterns and descriptions of the RA populations
evaluated across all 5 placebo-controlled trials are discussed in the
section below. Differences in study-specific data by randomized
treatment group are discussed where relevant.

#### Subject Disposition

Table 4-7 displays the subject disposition across all 5
placebo-controlled trials. Among the 2953 subjects randomized, 2932
(99%) received study drug. Overall, the study withdrawal rates were
approximately 25% with the most frequently reported reason for early
withdrawal being an adverse event (AE). In the MTX Combination Study
(960180), the Confirmatory Efficacy Study (990145), and the Safety Study
(990757), withdrawal due to AEs was more common among anakinra treated
subjects in comparison with placebo subjects, however, this difference
is primarily due to ISRs. Other notable differences include the
withdrawal rates due to lack of efficacy or disease progression, which
was generally more common in the placebo groups or among the lower
anakinra doses. In the Safety Study (990757), 4 anakinra subjects (0.4%)
and 1 placebo subject (0.4%) were classified as having withdrawn as a
result of death. Within each of the 5 studies, the withdrawal patterns
were similar among the randomized treatment groups.

In the Monotherapy Study (0560), one subject was randomized (150 mg
group) but did not receive study drug. This subject was participating in
a magnetic resonance imaging (MRI) sub-study and upon receipt of
approximately 16 mL of contrast agent for a baseline MRI went into
anaphylactic shock. This event, and the subject's withdrawal, occurred
prior to receipt of study drug.

In the Low Dose Monotherapy Study (960182) and the MTX Combination Study
(960180) all randomized subjects received at least 1 dose of study drug.

In the Confirmatory Efficacy Study (990145), 5 subjects were randomized
but did not receive study drug. Three of these subjects had study drug
withheld due to medical conditions discovered after randomization, one
subject discontinued their NSAIDs between screening and randomization,
and one subject was lost to follow-up. As the blind for individual
subjects remains intact, the randomized treatment groups for these
individual subjects are not available; however, based on the aggregate
results, 2 of these subjects were randomized to receive placebo and the
other 3 anakinra.

Fifteen of the 1414 subjects in the Safety Study (990757) were
randomized but never received study drug. Of the 15 subjects, 1 was
randomized to receive placebo (0.4%) and 14 to receive anakinra (1.2%).
Ten of these subjects withdrew consent, 3 were determined to be
ineligible, 1 subject was unable to demonstrate the ability to
self-inject, and 1 was lost to follow up.

Table 4‑7. Subject Disposition

+---+---+----------------------+--------+--------+-------+---------+------+
|   |   |                      | Study  |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   |                      | 0560   | 960182 | 9     | 990757  | 99   |
|   |   |                      |        |        | 60180 |         | 0145 |
+---+---+----------------------+--------+--------+-------+---------+------+
| T |   |                      | 473    | 141    | 419   | 1414    | 506  |
| o |   |                      |        |        |       |         |      |
| t |   |                      |        |        |       |         |      |
| a |   |                      |        |        |       |         |      |
| l |   |                      |        |        |       |         |      |
| r |   |                      |        |        |       |         |      |
| a |   |                      |        |        |       |         |      |
| n |   |                      |        |        |       |         |      |
| d |   |                      |        |        |       |         |      |
| o |   |                      |        |        |       |         |      |
| m |   |                      |        |        |       |         |      |
| i |   |                      |        |        |       |         |      |
| z |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| d |   |                      |        |        |       |         |      |
| - |   |                      |        |        |       |         |      |
| - |   |                      |        |        |       |         |      |
| n |   |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
| N |   |                      | 1      | 0      | 0     | 15      | 5    |
| e |   |                      |        |        |       |         |      |
| v |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| r |   |                      |        |        |       |         |      |
| r |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| c |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| i |   |                      |        |        |       |         |      |
| v |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| d |   |                      |        |        |       |         |      |
| d |   |                      |        |        |       |         |      |
| r |   |                      |        |        |       |         |      |
| u |   |                      |        |        |       |         |      |
| g |   |                      |        |        |       |         |      |
| - |   |                      |        |        |       |         |      |
| - |   |                      |        |        |       |         |      |
| n |   |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
| C |   |                      | 72.9   | 87.9   | 79.0  | 78.1    | 75.7 |
| o |   |                      |        |        |       |         |      |
| m |   |                      |        |        |       |         |      |
| p |   |                      |        |        |       |         |      |
| l |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| t |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| d |   |                      |        |        |       |         |      |
|   |   |                      |        |        |       |         |      |
| - |   |                      |        |        |       |         |      |
| % |   |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
| W |   |                      | 27.1   | 12.1   | 21.0  | 21.9    | 24.3 |
| i |   |                      |        |        |       |         |      |
| t |   |                      |        |        |       |         |      |
| h |   |                      |        |        |       |         |      |
| d |   |                      |        |        |       |         |      |
| r |   |                      |        |        |       |         |      |
| e |   |                      |        |        |       |         |      |
| w |   |                      |        |        |       |         |      |
|   |   |                      |        |        |       |         |      |
| - |   |                      |        |        |       |         |      |
| % |   |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
|   | R |                      |        |        |       |         |      |
|   | e |                      |        |        |       |         |      |
|   | a |                      |        |        |       |         |      |
|   | s |                      |        |        |       |         |      |
|   | o |                      |        |        |       |         |      |
|   | n |                      |        |        |       |         |      |
|   | f |                      |        |        |       |         |      |
|   | o |                      |        |        |       |         |      |
|   | r |                      |        |        |       |         |      |
|   | w |                      |        |        |       |         |      |
|   | i |                      |        |        |       |         |      |
|   | t |                      |        |        |       |         |      |
|   | h |                      |        |        |       |         |      |
|   | d |                      |        |        |       |         |      |
|   | r |                      |        |        |       |         |      |
|   | a |                      |        |        |       |         |      |
|   | w |                      |        |        |       |         |      |
|   | a |                      |        |        |       |         |      |
|   | l |                      |        |        |       |         |      |
|   |   |                      |        |        |       |         |      |
|   | - |                      |        |        |       |         |      |
|   | % |                      |        |        |       |         |      |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   | Adverse event        | 17.3   | 5.7    | 7.2   | 10.4    | 10.9 |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   | Lack of efficacy     | 5.5    | 3.5    | 8.4   | 1.3     | 2.6  |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   | Other                | 4.2    | 2.8    | 5.5   | 9.9     | 10.9 |
+---+---+----------------------+--------+--------+-------+---------+------+
|   |   | Death                | 0.0    | 0.0    | 0.0   | 0.3     | 0.0  |
+---+---+----------------------+--------+--------+-------+---------+------+
| / |   |                      |        |        |       |         |      |
| s |   |                      |        |        |       |         |      |
| t |   |                      |        |        |       |         |      |
| a |   |                      |        |        |       |         |      |
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| 1 |   |                      |        |        |       |         |      |
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| / |   |                      |        |        |       |         |      |
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| n |   |                      |        |        |       |         |      |
| a |   |                      |        |        |       |         |      |
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| y |   |                      |        |        |       |         |      |
| s |   |                      |        |        |       |         |      |
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| s |   |                      |        |        |       |         |      |
| / |   |                      |        |        |       |         |      |
| a |   |                      |        |        |       |         |      |
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| s |   |                      |        |        |       |         |      |
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+---+---+----------------------+--------+--------+-------+---------+------+

#### Baseline Subject Characteristics, Disease Status, and RA Medications

Summary statistics for baseline subject demographics, disease status and
RA medications are shown in Table 4-4, Table 4-5, and Table 4-6
respectively. In general, subjects had similar demographic profiles
across the 5 studies, and are representative of the typical RA
population. The majority of the subjects were Caucasian women, with a
mean age ranging from 52 to 56 years, weighing on average approximately
75 kg at study entry (Table 4-8).

Table 4‑8. Baseline Demographics

+-----------------+---------+---------+---------+---------+---------+---+
|                 | Study   |         |         |         |         |   |
+-----------------+---------+---------+---------+---------+---------+---+
|                 | 0560    | 960182  | 960180  | 990757  | 990145  |   |
+-----------------+---------+---------+---------+---------+---------+---+
| Mean            | (N =    | (N =    | (N =    | (N =    | (N =    |   |
|                 | 472)    | 141)    | 419)    | 1399)   | 501)    |   |
+-----------------+---------+---------+---------+---------+---------+---+
| Female - %      | 75.0    | 76.6    | 77.6    | 74.7    | 77.0    |   |
+-----------------+---------+---------+---------+---------+---------+---+
|                 |         |         |         |         |         |   |
+-----------------+---------+---------+---------+---------+---------+---+
| Caucasian - %   | 98.7    | 100.0   | 88.5    | 88.3    | 86.8    |   |
+-----------------+---------+---------+---------+---------+---------+---+
|                 |         |         |         |         |         |   |
+-----------------+---------+---------+---------+---------+---------+---+
| Age (yr)        | 53.1    | 52.2    | 52.5    | 54.8    | 56.3    |   |
+-----------------+---------+---------+---------+---------+---------+---+
|                 |         |         |         |         |         |   |
+-----------------+---------+---------+---------+---------+---------+---+
| Weight (kg)     | 69.6    | 70.1    | 78.6    | 76.8    | 81.1    |   |
+-----------------+---------+---------+---------+---------+---------+---+
| /stat/il        |         |         |         |         |         |   |
| 1ra/fda_slides/ |         |         |         |         |         |   |
| analysis/allstu |         |         |         |         |         |   |
| dy/statfiles/ta |         |         |         |         |         |   |
| bles/t_base.sas |         |         |         |         |         |   |
|                 |         |         |         |         |         |   |
| Output:         |         |         |         |         |         |   |
| t_bas           |         |         |         |         |         |   |
| e_demog_all.rtf |         |         |         |         |         |   |
| (generated      |         |         |         |         |         |   |
| 05JUN2001)      |         |         |         |         |         |   |
+-----------------+---------+---------+---------+---------+---------+---+

As shown in Table 4-9, subjects participating in each of these 5 studies
had clear evidence of active RA at baseline. Given the various
inclusion/exclusion criteria, it is not unexpected to observe slight
variations among the 5 studies; however, in general, the over 2900
subjects had moderate to severe RA. On average subjects had from 23 to
34 tender/painful joints and 18 to 26 swollen joints, as well as
elevated ESR values at baseline (Table 4-9). As expected, baseline CRP
values were generally lower in the 3 trials (960180, 990145, and 990757)
that permitted concomitant MTX therapy.

Table 4-10 describes the RA medications at baseline. Approximately 40%
to 65% of subjects were taking corticosteroids at baseline. The majority
of subjects (\> 70%) were taking baseline NSAIDs. The only variable in
RA medications are with MTX and other DMARDS. These differences were
protocol defined, with study 990757 as the only study that allowed
inclusion of DMARDS other than MTX. With the exception of differences
noted above, within each of the individual studies, baseline
demographics, disease status and RA medications were well-balanced among
the randomized treatment groups.

Table 4‑9. Baseline Disease Status

+-------------------------+--------+-------+-------+-------+--------+---+
|                         | Study  |       |       |       |        |   |
+-------------------------+--------+-------+-------+-------+--------+---+
|                         | 0560   | 9     | 9     | 9     | 990145 |   |
|                         |        | 60182 | 60180 | 90757 |        |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Mean                    | (N =   | (N =  | (N =  | (N =  | (N =   |   |
|                         | 472)   | 141)  | 419)  | 1399) | 501)   |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Duration of RA (yr)     | 4.0    | 3.5   | 7.4   | 10.3  | 10.8   |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Tender/Painful (0 - 68) | 34.3   | 33.0  | 25.4  | 22.6  | 25.6   |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Swollen (0 - 66)        | 26.1   | 23.7  | 18.3  | 18.7  | 20.0   |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| HAQ (0 - 3)             | 1.57   | 1.64  | 1.40  | 1.41  | 1.34   |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Physician\'s global     | 77.1   | 78.0  | 57.4  | 53.7  | 57.2   |   |
| (0 - 100)               |        |       |       |       |        |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Subject\'s global (0 -  | 76.7   | 77.5  | 50.2  | 53.0  | 52.7   |   |
| 100)                    |        |       |       |       |        |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Subject\'s pain (0 -    | 62.9   | 59.9  | 50.8  | 55.5  | 57.4   |   |
| 100)                    |        |       |       |       |        |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| CRP (mg/dL)             | 4.14   | 3.17  | 1.91  | 2.67  | 2.63   |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| ESR (mm/hr)             | 49.5   | 43.2  | 36.7  | N/A   | 42.2   |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| Morning stiffness       | 134.2  | 127.4 | 130.2 | N/A   | 106.5  |   |
| (min/day)               |        |       |       |       |        |   |
+-------------------------+--------+-------+-------+-------+--------+---+
| /stat/il1ra/fda_slides  |        |       |       |       |        |   |
| /analysis/allstudy/stat |        |       |       |       |        |   |
| files/tables/t_base.sas |        |       |       |       |        |   |
|                         |        |       |       |       |        |   |
| Output:                 |        |       |       |       |        |   |
| t_base_disease_all.rtf  |        |       |       |       |        |   |
| (generated 10MAY2001)   |        |       |       |       |        |   |
+-------------------------+--------+-------+-------+-------+--------+---+

Table 4‑10. Baseline RA Medications

  -------------------------- -------- --------- -------- --------- --------
                             Study                                 

                             0560     960182    960180   990757    990145

                             (N =     (N = 141) (N =     (N =      (N =
                             472)               419)     1339)     501)

  Corticosteroid use at      42.6     44.0      64.2     57.8      52.7
  baseline - %                                                     

  NSAIDs use at baseline - % 83.5     85.8      69.0     87.0      76.4

  MTX alone use at           0%       0%        100%     31.1%     100%
  baseline - %                                                     

  Other DMARD excluding MTX  0%       0%        0%       25.4%     0%
  use at baseline - %                                              

  MTX + other DMARD use at   0%       0%        0%       22.3%     0%
  baseline %                                                       
  -------------------------- -------- --------- -------- --------- --------

## Clinical Data - Efficacy

Efficacy results from the Monotherapy Study (0560), the Low Dose
Monotherapy Study (960182), the MTX Combination Study (960180), and the
Confirmatory Efficacy Study (990145) to support the signs and symptoms
indication for anakinra are summarized separately for each study,
followed by a review of the radiographic results for the Larsen and
modified Sharp scores from the Monotherapy Study (0560).

### Signs and Symptoms Data

The analysis of signs and symptoms data for the Confirmatory Efficacy
Study (990145) confirmed the efficacy results seen in the Monotherapy
Study (0560), and the MTX Combination Study (960180). After treatment
with 100 mg/day anakinra, subjects were more likely to achieve
symptomatic improvements of 20% or more by week 24 in comparison with
placebo subjects, p \< 0.001. The onset of action was rapid and
sustained throughout the 24-week treatment period.

#### Monotherapy Study (0560)

The results for the prespecified analysis (M-ITT with LOCF imputation)
of the primary endpoint, the ACR~20~ at week 24, are displayed in
Figure 4-6. Anakinra subjects were more likely to achieve an ACR~20~
response at week 24 than were placebo subjects. The proportion of
subjects achieving an ACR~20~ response in the placebo group was 27%
compared to response rates of 39%, 34%, and 43% for the 30, 75, and 150
mg anakinra dose groups, respectively (upper panel, Figure 4-6). While a
clear dose response was not observed, and statistical significance was
not attained at the 75 mg dose, the results for both the 30 mg and 150
mg doses were statistically different from placebo, p = 0.047 and
p = 0.014, respectively. The original protocol did not specify an
adjustment for multiple comparison; nevertheless, the observed
statistical superiority over placebo for the 150 mg dose group was
maintained even when adjustments for multiple comparisons were made at
an adjusted two-tailed alpha level of 0.019 (Dunnett's multiple
comparison adjustment: 3 comparisons to placebo).

Additional analyses for the primary endpoint using the ITT subset (all
subjects receiving at least one dose of study drug) with a non-responder
imputation for missing data were also conducted. The ITT analyses
include the 4 subjects excluded from the M-ITT subset due to missing
postbaseline assessments. The results from the ITT analysis (lower
panel, Figure 4-6), continue to demonstrate statistically significant
effects for the 30 and 150 mg dose groups compared to placebo. When
adjusted for multiple comparisons the nominal p-values were greater than
the adjusted alpha level of 0.019.

From Figure 4-7 (upper panel), the effect of anakinra is shown to be
rapid with clinically and statistically significant differences observed
as early as week 2. When compared to placebo, anakinra subjects were
also more than twice as likely to sustain their improvements, a result
observed for each anakinra dose, p \< 0.01 (middle panel, Figure 4-7).
The magnitude of improvement was also greater among anakinra subjects.
Examination of the week 24 ACR~50~ response rates reveals that subjects
in both the 30 and 150 mg dose groups were more than twice as likely to
achieve improvements of 50% or more compared to subjects receiving
placebo, p \< 0.05 (lower panel, Figure 4-7).

Examination of the individual ACR components revealed a pattern of
effect very similar to that observed for the ACR composite score. From
Figure 4-8, it is clear that anakinra treated subjects achieved rapid
improvements in all components with statistically significant effects
observed at week 24 for the 150 mg dose group with respect to every
component examined, p \< 0.05.

Figure 4‑6. Study 0560 - Proportion of Subjects Achieving an ACR~20~
Response at\
Week 24

M-ITT With LOCF Imputation

![](media/image7.wmf){width="3.998611111111111in" height="2.25in"}

ITT With Non-Responder Imputation

![](media/image8.wmf){width="3.998611111111111in" height="2.25in"}

Figure 4‑7. Study 0560 - ACR Composite Scores

![](media/image9.wmf){width="3.998611111111111in"
height="2.5527777777777776in"}

![](media/image10.wmf){width="3.998611111111111in"
height="2.5527777777777776in"}

![](media/image11.wmf){width="3.998611111111111in"
height="2.5527777777777776in"}

Figure 4‑8. Study 0560 -- Individual ACR Components Change From Baseline

![](media/image12.wmf){width="8.396527777777777in"
height="5.363888888888889in"}

####### Sensitivity Analyses {#sensitivity-analyses .FlushLeftBold .unnumbered}

Sensitivity analyses were conducted to determine the robustness of the
signs and symptoms results from the Monotherapy Study (0560),
specifically, to assess the potential impact of any inadvertent
unblinding that may have occurred as a result of Injection Site
Reactions (ISRs). As shown in Section 4.5.3.2, ISRs occur more
frequently, although not exclusively, in the anakinra treatment groups
and are dose-dependent.

To evaluate the treatment effect of anakinra in the absence of any
influence due to ISRs, the ACR~20~ response rates between anakinra and
placebo treated subjects were examined within the subset of subjects who
never experienced an ISR. This ISR-negative subset would be a group of
subjects, for whom, presumably, the blind remained intact. The results
of this analysis suggested that anakinra retained its clinical advantage
over placebo for both the ACR~20~ responses at week 24 and the sustained
ACR~20~ responses. Although the sample sizes were reduced in this
smaller ISR-negative subset, clear trends were consistently evident, and
for the sustained response, results reached statistical significance. As
in the primary analysis, efficacy was most consistent at the higher
anakinra dose of 150 mg (Appendix 4- 2 and Appendix 4-3).

Although ISRs were more common among subjects treated with anakinra, the
results from this analysis indicate the presence of ISRs did not unduly
influence the results and are supportive of the study's overall
conclusion: anakinra is effective in reducing the signs and symptoms of
RA.

#### Low Dose Monotherapy (960182)

None of the anakinra dose groups (2.5, 10 and 30 mg/day) examined in the
Low Dose Monotherapy Study (960182) demonstrated a statistically
significant difference from placebo with respect to the ACR~20~ response
rates at week 12, the study's primary endpoint (Figure 4-9). The lack of
an effect for anakinra was observed for each efficacy endpoint examined.
Further examination to determine if these results were due to baseline
covariates, subject disease characteristics, or potential safety issues
did not reveal any explanation for the lack of an effect. Relative to
placebo, anakinra subjects did not appear to have worsening signs and
symptoms scores; however, at these lower doses, anakinra subjects were
unable to achieve improvements over and beyond those observed for
placebo subjects.

Figure 4‑9. Study 960182 -- Proportion of Subjects Achieving an ACR~20~
Response at Week 12

ITT With Non-Responder Imputation

![](media/image13.wmf){width="3.998611111111111in"
height="2.354861111111111in"}

#### MTX Combination Study (960180)

There was a highly significant dose-response between ACR~20~ response
rates and anakinra dose at week 12, the study's primary endpoint, and
week 24, p = 0.001 and p = 0.004, respectively (Figure 4-10). Although
not strictly linear, the results clearly indicate that increasing
ACR~20~ response rates are associated with higher anakinra doses.

The ACR~20~ response rate for each time point examined for the placebo,
and the higher anakinra doses of 0.4, 1.0 and 2.0 mg/kg dose groups are
displayed in Figure 4-11 (upper panel). For clarity only the higher dose
groups are shown; see Appendix 4-4 for the lower dose groups. As
observed in the Monotherapy Study (0560), compared with placebo, there
is a clear indication that anakinra achieves a rapid response that is
maintained throughout the treatment period. The sustained ACR~20~
response rates (middle panel, Figure 4-11), are also consistent with
those observed in the Monotherapy Study (0560). Anakinra subjects at the
1.0 and 2.0 mg/kg doses were more than twice as likely to sustain their
ACR~20~ improvements when compared with placebo subjects, p = 0.039 and
p = 0.013, respectively. Higher magnitudes of improvement in the ACR
composite score were also associated with higher anakinra doses as
evidenced by the overall test for dose-response, p = 0.003 (lower panel,
Figure 4-11). This was most evident at the 1.0 mg/kg dose group, where
24% anakinra subjects achieved an ACR~50~ and 10% an ACR~70~, p \< 0.05,
when compared to placebo.

Examination of the individual ACR components graphically displayed in
Figure 4-12 indicates an advantage for anakinra subjects over placebo
subjects at the higher anakinra doses[^1]. At week 24, the prespecified
time point for the individual ACR components, statistically significant
differences between placebo and the 1.0 and 2.0 mg/kg doses were
observed for HAQ, the physician's and subject's global assessment,
subject's pain assessment, and ESR. It should be noted that in this
study, 49.9% of subjects had baseline CRP levels within the normal range
(0 to 0.8 mg/dL) where all subjects were receiving concomitant MTX
therapy.

Figure 4‑10. Study 960180 -- Proportion of Subjects Achieving an ACR~20~
Response

Week 12\
ITT With Non-Responder Imputation

![](media/image14.wmf){width="3.998611111111111in" height="2.25in"}

Week 24\
ITT With Non-Responder Imputation

![](media/image15.wmf){width="3.998611111111111in" height="2.25in"}

Figure 4‑11. Figure Study 960180 - ACR Composite Scores

![](media/image16.wmf){width="3.998611111111111in"
height="2.5527777777777776in"}

![](media/image17.wmf){width="3.998611111111111in"
height="2.5527777777777776in"}

![](media/image18.wmf){width="3.998611111111111in"
height="2.5527777777777776in"}

Figure 4‑12. Study 960180 -- Individual ACR Components Change From
Baseline

![](media/image19.wmf){width="8.207638888888889in"
height="5.333333333333333in"}

####### Sensitivity Analyses {#sensitivity-analyses-1 .FlushLeftBold .unnumbered}

As in the Monotherapy Study (0560), sensitivity analyses were conducted
to examine the robustness of the results, particularly with regard to
potential unblinding due to ISRs (Appendix 4-5, Appendix 4-6 and
Appendix 4-7). Using a methodology similar to that used in the
Monotherapy Study (0560), the analyses examined the ACR~20~ results at
week 12 and 24, as well as the sustained ACR~20~ results for the cohort
of subjects who had not experienced an ISR by the time the ACR
assessment was made (either week 12 or week 24). The results of these
sensitivity analyses are similar to those observed in the Monotherapy
Study (0560). Among those subjects who did not experience an ISR,
anakinra treated subjects, most notably at the 1.0 mg/kg dose group
continued to do significantly better than placebo subjects with respect
to an ACR~20~ response at both weeks 12 and 24, (p \< 0.05 and
p \< 0.01, respectively). Results for the ACR~20~ sustained response
were similar to those observed in the primary analysis for this study.
Despite the smaller sample size for the subset of subjects with no ISRs,
the proportion of subjects achieving a sustained improvement of at least
20% or more was greater in the 1.0 and 2.0 mg/kg anakinra dose groups
compared with placebo subjects, (43% in both anakinra groups vs. 17% for
placebo, p = 0.035, and p = 0.076, respectively). The results of these
sensitivity analyses support the stable and robust nature of the overall
study findings that anakinra is an effective treatment for the signs and
symptoms of RA.

#### Confirmatory Efficacy Study (990145)

The Confirmatory Efficacy Study (990145; N = 501) confirmed that the
proposed dose of 100 mg/day is effective in reducing the signs and
symptoms. Subjects treated with 100 mg/day of anakinra plus background
MTX were more likely to achieve an ACR~20~ response at week 24, the
prespecified confirmatory endpoint for signs and symptoms, than subjects
treated with placebo and background MTX, p \< 0.001 (Figure 4-13). In
addition, clinically and statistically meaningful effects for each of
the secondary signs and symptoms endpoints were also achieved. The
effects of anakinra were rapid and sustained throughout the 24-week
treatment period. Anakinra subjects were also able to achieve higher
magnitudes of improvements, being twice as likely to achieve an ACR~50~,
and almost three times as likely to achieve an ACR~70~ than placebo
subjects receiving MTX alone.

####### ACR~20~ Response {#acr20-response .FlushLeftBold .unnumbered}

Figure 4-13 displays the results of ACR~20~ at week 24, the primary
endpoint for signs and symptoms of RA. Subjects receiving 100 mg
anakinra plus MTX showed clinically and statistically significant
improvement in the signs and symptoms of their RA at week 24 relative to
subjects receiving placebo plus MTX as measured by the ACR~20~ score. Of
the 250 anakinra treated subjects included in the analysis, 38% achieved
a minimum of 20% improvement in the ACR composite score compared with
22% of subjects receiving placebo (p \< 0.001). The odds ratio of
achieving a response in the anakinra group relative to the placebo group
was 2.36 (95% confidence interval: 1.55, 3.62).

Figure 4‑13. Percent of Subjects Achieving an ACR~20~ Response at Week
24

ITT With Non-responder Imputation

![](media/image20.wmf){width="3.998611111111111in"
height="2.354861111111111in"}

Anakinra's effects on ACR~20~ had an early onset of action, as reflected
in Figure 4-14 which shows the ACR~20~ response at each study visit.
Anakinra subjects had a 2‑fold higher ACR~20~ response than placebo
subjects by the first study visit at week 4, with values of 21% compared
with 11%, respectively (p = 0.004). The clinical and statistical
superiority of anakinra to placebo was maintained for each time point
examined throughout the 24-week treatment period.

Figure 4‑14. Percent of Subjects Achieving an ACR20 Response by Study
Week

ITT With Non-responder Imputation

![](media/image21.wmf){width="5.021527777777778in"
height="2.957638888888889in"}

Anakinra subjects were more than twice as likely as placebo subjects to
achieve a sustained ACR~20~ response, Figure 4-15. Among anakinra
subjects, 27% achieved a sustained response during the 24-week analysis
period, compared with 12% of placebo subjects, p \< 0.001. The odds
ratio of achieving a sustained response was 3.43 (95% confidence
interval: 2.05, 5.90) in favor of anakinra over placebo.

Figure 4‑15. Percent of Subjects Achieving a Sustained ACR~20~ Response

ITT With Non-responder Imputation

![](media/image22.wmf){width="3.998611111111111in"
height="2.354861111111111in"}

####### ACR~50~ and ACR~70~ Responses {#acr50-and-acr70-responses .FlushLeftBold .unnumbered}

Improvements of 50% and 70% in the symptoms of RA were observed more
frequently among subjects receiving anakinra than for those receiving
placebo (p \< 0.001 and p = 0.024). The percentage of subjects achieving
ACR~50~ and ACR~70~ at week 24 is graphically presented in Figure 4-16.

More than twice as many anakinra-treated subjects achieved ACR~50~
responses at week 24 (17%) compared with placebo subjects (8%),
p \< 0.001. The odds ratio of achieving a response was 2.61 for anakinra
subjects in comparison with placebo (95% confidence interval: 1.46,
4.84).

In addition to achieving improvements of 50% or more, anakinra subjects
were almost three times more likely to achieve improvements of at least
70% compared with subjects receiving placebo (6% and 2%; respectively,
p = 0.024).

Figure 4‑16. Percent of Subjects by ACR Level of Improvement at Week 24

ITT With Non-responder Imputation

![](media/image23.wmf){width="3.998611111111111in"
height="2.354861111111111in"}

In summary, anakinra demonstrated a clinically and statistically
significant advantage over placebo in ACR~20~ response at week 24.
Further, anakinra showed an early onset of action, with a 2-fold
advantage in ACR~20~ response evident by the first visit at week 4.
Anakinra subjects were more than twice as likely as placebo subjects to
have a durable improvement in the signs and symptoms of their RA as
measured by the ACR~20~ sustained response. Finally, higher levels of
relief as reflected in both the ACR~50~ and ACR~70~ endpoints were more
than twice as likely for anakinra subjects as placebo subjects.

####### Individual ACR components at 24 Weeks {#individual-acr-components-at-24-weeks .FlushLeftBold .unnumbered}

The results for individual ACR components are shown in Figure 4-17. The
time course of change in the signs and symptoms of RA generally
demonstrate progressive improvement over the 24 weeks for subjects
receiving anakinra, with early onset of improvement evident in all
components of signs and symptoms.

Anakinra subjects experienced clinically and statistically significant
improvement relative to placebo in all ACR components with the exception
of the swollen joint count which did not achieve statistical
significance at week 24, the prespecified time point (see Appendix 4-8).
The largest between-treatment differences at week 24 were apparent for
the objective endpoints of CRP and ESR. The decrease in log-transformed
CRP was 5 times larger for anakinra subjects (-0.51) than for placebo
subjects (-0.10; p \< 0.001), and the decrease in ESR was almost 3 times
larger (-16.19 vs -5.98 mm/hr, respectively; p \< 0.001). The assessment
of the tender/painful joint count indicated a 39% larger reduction from
baseline with anakinra treatment (a mean improvement of -12.00 joints)
than with placebo (-8.65 joints; p = 0.006). Subjects receiving anakinra
experienced an improvement of -0.29 in disability status (HAQ) by week
24, a 61% better response than the improvement of -0.18 seen in the
placebo group (p = 0.017). The physician's and subject's assessments of
disease and subject's assessment of pain also show clinically and
statistically significant advantages for anakinra therapy (p = 0.012,
p \< 0.001 and p = 0.003, respectively).

Figure 4‑17. Study 990145 Individual ACR Components Change From Baseline

![](media/image24.wmf){width="8.207638888888889in"
height="5.165972222222222in"}

####### Sensitivity Analyses {#sensitivity-analyses-2 .FlushLeftBold .unnumbered}

This section presents the results of 3 sensitivity analyses designed to
assess the robustness of the primary analysis for signs and symptoms in
the Confirmatory Efficacy Study (990145). The first analysis, the
completers analysis, examines the effect of missing signs and symptoms
data on the week-24 ACR~20~ response rates for each treatment group. The
second sensitivity analysis examines the potential effect of increased
on-study DMARD/corticosteroid use, while the final sensitivity analysis
examines the potential impact of inadvertent unblinding due to ISRs on
the assessment of signs and symptoms. Overall, the results of these
analyses indicate that the observed ACR~20~ response favoring anakinra
in the primary analysis is robust and consistent.

Table 4-11 summarizes the week-24 ACR~20~ results for the completer
subset. This analysis excludes subjects who were missing ACR~20~
responses at week 24 due to early withdrawal from study drug, a missed
visit, or incomplete assessments. Of the total sample of 501 subjects,
387 (77.2%) had observed ACR~20~ responses at week 24 and are included
in the completer analysis presented in Table 4-11. The remaining
114 subjects (22.8%) had missing or incomplete assessments at week 24
and are excluded from the completers analysis.

The results of the completers analysis demonstrate a clear treatment
advantage for anakinra similar to that seen in the primary analysis. The
ACR~20~ at week 24 was 29.4% for placebo and 47.0% for anakinra, with an
odds ratio of 2.31 (95% confidence interval: 1.47, 3.68) in favor of
anakinra (p \< 0.001). Thus, these results show that the conclusions
drawn from the primary analysis are not changed by the imputation of
missing signs and symptoms data.

Figure 4‑18. Percent of Subjects Achieving an ACR~20~ Response at Week
24\
Completer Analysis

![](media/image25.wmf){width="6.135416666666667in"
height="3.7534722222222223in"}

An important feature of the 990145 study design was the rules governing
the use of corticosteroids and DMARDs thought to affect the signs and
symptoms of RA without substantial effect on underlying structural
damage. A subset of such medications was permitted under certain
circumstances (Section 4.3.1.4). Regardless of the reasons for increased
corticosteroid or DMARD use, subjects who increased their exposure from
baseline levels were defined as non-responders from the time of increase
onwards. Exceptions included subjects receiving the medication
topically, rectally, opthalmically, as an inhalant, or by
intra-articular injection (which resulted in censoring of the affected
joint); administration by these routes was not considered to affect the
assessment of signs and symptoms. Subjects with missing ACR responses
were defined as non-responders regardless of their corticosteroid or
DMARD use. Table 4-11 displays the number of subjects with observed
ACR~20~ responses at week 24 who were determined to have increased their
steroid or DMARD use on or before week 24. Among subjects with observed
week-24 assessments, only 38 subjects, 19 subjects (7.6%) in each
treatment group, increased their steroid or DMARD exposure on study. Of
these, most subjects were found to be non-responders in their actual
assessments at week 24: 94.7% and 78.9% in the placebo and anakinra
groups, respectively (Table 4-11). Hence, the increases in the use of
steroids or DMARDs would be expected to have little impact on the
primary results, a conclusion that is confirmed by the analysis. When
the observed week-24 ACR~20~ responses are analyzed for the 38 subjects
(Table 4-12) who increased their on-study corticosteroids or DMARDs,
implementing the non-responder imputation for only those subjects with
missing 24-week values, the results remain essentially unchanged from
the primary analysis, with significantly higher response in the anakinra
group (39.2%) than in the placebo group (22.3%; p \< 0.001) and an odds
ratio favoring anakinra of 2.48 (95% confidence interval: 1.63, 3.81).

Table 4‑11. Summary of ACR~20~ Response at Week 24 for Completers\
Who Increased Corticosteroids or DMARDs From Baseline

  ------------- ----------------- ---------------- -- ------------ ---------------------------------- --------- -------- -- ---------- -------- --
                                                                                                      Placebo               Anakinra            

                                                                                                      (N = 251)             (N = 250)           

  Number of                                                                                           19        (7.6)       19         (7.6)    
  completers                                                                                                                                    
  with                                                                                                                                          
  increased                                                                                                                                     
  medications                                                                                                                                   

                                  Observed ACR~20~                                                                                              
                                  response at week                                                                                              
                                  24^a^                                                                                                         

                                                                   Nonresponder                       18        (94.7)      15         (78.9)   

                                                                   Responder                          1         (5.3)       4          (21.1)   

                                  Reasons for                                                                                                   
                                  increased                                                                                                     
                                  medications^a^                                                                                                

                                                                   Lack of efficacy criteria          8         (42.1)      5          (26.3)   

                                                                   Other^b^                           11        (57.9)      14         (73.7)   

  N =                                                 Number of                                                                                 
                                                      subjects who                                                                              
                                                      were                                                                                      
                                                      randomized                                                                                
                                                      as of 18 May                                                                              
                                                      2000 and who                                                                              
                                                      received                                                                                  

                                                      at least 1                                                                                
                                                      dose of                                                                                   
                                                      study drug                                                                                

  ^a^           Percents are                                                                                                                    
                based on the                                                                                                                    
                number of                                                                                                                       
                completers with                                                                                                                 
                increased                                                                                                                       
                medications.                                                                                                                    

  ^b^           Includes protocol                                                                                                               
                deviations and                                                                                                                  
                subjects who                                                                                                                    
                increased                                                                                                                       
                corticosteroids                                                                                                                 
                according to                                                                                                                    

                protocol                                                                                                                        
  ------------- ----------------- ---------------- -- ------------ ---------------------------------- --------- -------- -- ---------- -------- --

Table 4‑12. Percent of Subjects Achieving an ACR~20~ Response at\
Week 24 Using Non-responder Imputation Only for Missing Data

  ------------ -- ------------ -------------------------------- --------- -------- ------ ---------- -------- --
                                                                Placebo                   Anakinra            

                                                                (N = 251)                 (N = 250)           

  Number of                                                     251                       250                 
  subjects                                                                                                    
  included in                                                                                                 
  analysis                                                                                                    

  Number of                                                     56        (22.3)          98         (39.2)   
  responders                                                                                                  
  (%)                                                                                                         

  Odds ratio                                                                              2.48                

  95%                                                                                     (1.63,              
  confidence                                                                              3.81)               
  interval for                                                                                                
  odds ratio                                                                                                  

  p-value                                                                                 \< 0.001            

  N =             Number of                                                                                   
                  subjects who                                                                                
                  were                                                                                        
                  randomized                                                                                  
                  as of 18 May                                                                                
                  2000 and who                                                                                
                  received                                                                                    

                  at least 1                                                                                  
                  dose of                                                                                     
                  study drug                                                                                  

  Odds ratio                                                                                                  
  is a ratio                                                                                                  
  of the odds                                                                                                 
  of achieving                                                                                                
  an ACR                                                                                                      
  response                                                                                                    
  compared to                                                                                                 
  placebo                                                                                                     

                  using a                                                                                     
                  logistic                                                                                    
                  regression                                                                                  
                  adjusted for                                                                                
                  center.                                                                                     
  ------------ -- ------------ -------------------------------- --------- -------- ------ ---------- -------- --

The final sensitivity analysis assesses the potential unblinding effects
of ISRs on the evaluation of signs and symptoms. Although the protocol
required assessors to be blinded to application site events, ISRs were
the most frequent class of adverse events related to anakinra, and it is
theoretically possible that the presence or absence of ISRs may have
affected the study blind. To assess the impact of any potential effect,
the ACR~20~ response rates between the placebo and anakinra groups were
compared within 2 subsets: subjects who experienced 1 or more ISRs
during the study and those who did not experience an ISR (Table 4-13).
The resulting ACR~20~ response rates favor anakinra over placebo in
subjects with and without ISRs. Among subjects without ISRs, in whom the
blind presumably remained intact, the response rates of 19.3% and 36.8%
for placebo and anakinra, respectively, were very similar to the
corresponding rates of 22% and 38% seen in the primary analysis
(Figure 4-13), and the difference between treatments was statistically
significant (p = 0.002). Among subjects with ISRs, the response
numerically indicated a treatment advantage for anakinra over placebo.
Overall, these results suggest that the observed treatment effect
favoring anakinra in the primary analysis was not the result of
unblinding due to ISRs.

Table 4‑13. Percent of Subjects Achieving an ACR~20~ Response at Week
24\
by Injection Site Reaction (ISR) Using Non-responder Imputation

  ---------- -- ------------ ----------------------------- --------- -------- -- ---------- -------- -- ------------ -------
                                                           Placebo               Anakinra               Chi-square   

                                                           (N = 251)             (N = 250)              p-value      

  Subjects                                                                                                           
  without                                                                                                            
  ISR                                                                                                                

                n                                          192                   87                                  

                Number of                                  37        (19.3)      32         (36.8)                   0.002
                responders                                                                                           
                (%)                                                                                                  

                                                                                                                     

  Subjects                                                                                                           
  with ISR                                                                                                           

                n                                          59                    163                                 

                Number of                                  18        (30.5)      62         (38.0)                   0.302
                responders                                                                                           
                (%)                                                                                                  

  N =           Number of                                                                                            
                subjects who                                                                                         
                were                                                                                                 
                randomized                                                                                           
                as of 18 May                                                                                         
                2000 and who                                                                                         
                received                                                                                             

                at least 1                                                                                           
                dose of                                                                                              
                study drug                                                                                           
  ---------- -- ------------ ----------------------------- --------- -------- -- ---------- -------- -- ------------ -------

### Monotherapy Study (0560): Radiographic Data

An important prespecified secondary efficacy endpoint in the Monotherapy
Study (0560) was the Larsen score, a measure of radiographic disease
progression. In addition to the prespecified Larsen score, these
radiographs were subsequently re-examined by an independent assessor,
and re-scored using the Modified Sharp score. The methods and results
for these radiographic endpoints are discussed below.

#### Radiographic Endpoints: Larsen and Modified Sharp Scores

The Larsen and modified Sharp was designed earlier and modified in the
1970's, and modifications of these methods are the most widely accepted
methods in use today for assessing progression of joint damage in RA.
The Larsen score is a single global composite score of overall damage
assesses both erosions and cartilage destruction simultaneously.

In contrast, the modified Sharp scoring method formally distinguishes
2 aspects of joint damage; an erosion score (ES) and a joint space
narrowing (JSN) score are calculated separately, and then added to
provide a total modified Sharp score.

Both scoring methods thus provide a single composite measure of overall
joint damage, with the modified Sharp score providing additional
information that allows further assessment of erosions and joint space
narrowing separately. Since the Larsen scoring method gained wide
acceptance in Europe, where it was originally devised, it was the
scoring method chosen prospectively for use in the Monotherapy Study
(0560) and its extension (0564). The Sharp scoring method is considered
more sensitive and is the most widely accepted scoring method in the
United States.^61,62^ Consequently, the radiographs for the Monotherapy
Study (0560) were reanalyzed using a modified Sharp scoring method.

Radiographs were viewed and scored according to the protocol using the
Larsen method (Table 4-14) by 2 consulting radiologists (Drs Iain Watt
and Mark Cobby, University of Bristol, UK) who were blinded to subject
identification, treatment group, and chronology of radiographs. The
radiologists sat side by side to read the radiographs, with the Larsen
score categories and standard films on the view box next to the
subject's radiograph as a reference. Scores were assigned by comparison
with the series of standard radiographs. The radiologists reached
consensus when necessary, and always adopted the conservative (lower)
score when in doubt. The radiographs were graded individually and not in
pairs or triplicates.

Larsen's method as used here assesses global changes and grades
individual joints on a scale of 0 to 6 (Table 4-14).^63^ The composite
Larsen score is obtained by summing the scores for each of the joints
examined. Joint grades are based on the presence of pathologic findings
including both erosions and joint space narrowing, although the
predominant characteristic of joint damage that is scored by the Larsen
method relates to erosions.^64^ Thus, the Larsen score does not
distinguish between bone erosions and joint space narrowing. An erosion
was defined as a definite loss of cortical outline that was clearly
visualized at an appropriate site. Any possible erosion that was not
seen in profile was disregarded.

The Larsen scoring system used in this study included a modification to
the original Larsen scoring system added by the readers: A score of 6
was allocated to joints that had become fused (ankylosed).

Table 4‑14. The Larsen Scoring Method

  -------- --------------------------------------------------------------
  Score    Description
  ^a^      

  0        Normal

  1        Slight abnormality, including ≥ 1 of the following lesions:
           periarticular soft tissue swelling, periarticular
           osteoporosis, and slight joint space narrowing

  2        Definite early abnormality, including definite erosion, with
           or without joint space narrowing

  3        Medium destructive abnormality

  4        Severe destructive abnormality

  5        Mutilating abnormality (original articular surfaces have
           disappeared)

  6        Fused joint ^b^
  -------- --------------------------------------------------------------

^a^ Five areas are examined comprising 30 joints (15 per hand/wrist):
interphalangeal of digit I, distal and proximal interphalangeal of
digits II to V, metacarpo‑phalangeal of digits I to V, and the wrist.
Dislocation and bony ankylosis are considered; if present, the scoring
is based on the concomitant bone destruction. Maximum score of both
hands is 180.

^b^ This score, added by the readers, is a modification to the basic
Larsen method.

In contrast to the Larsen score, the modified Sharp score formally
distinguishes 2 aspects of joint damage. An erosion score (ES) and a
joint space narrowing (JSN) score are calculated separately by summing
the scores for individual joints, normalized to a scale of 0 to 100, and
then added to provide a total modified Sharp score (Table 4-15).

After the completion of the Monotherapy Study (0560) and its extension
(0564), the radiographs were collected from the study sites and supplied
to an outside consultant, Dr Harry Genant (University of California, San
Francisco), for scoring using a second validated scoring method, a
modified Sharp method.^69,70^ All radiographs for each subject were
scored together as pairs or triplicates, blinded to treatment group and
sequence. Radiographs were scored with the modified Sharp method if ≥ 2
radiographs were available per subject. Radiographs were also only
scored if they had been exposed adequately for interpretation. Some
radiographs were only partially scored because of the position of the
hand/wrist.

Table 4‑15. Modified Sharp (Genant) Scoring Method

  ------------- ------------------------- ----------- -------------------------
  Erosion ^a^                             Joint Space 
                                          Narrowing   
                                          ^b^         

  0             Normal                    0           Normal

  0.5           Questionable or subtle    0.5         Questionable or subtle
                change                                Change

  1             Mild                      1           Mild

  1.5           Mild worse                1.5         Mild worse

  2             Moderate                  2           Moderate

  2.5           Moderate worse            2.5         Moderate worse

  3             Severe                    3           Severe

  3.5           Severe worse              3.5         Severe worse

                                          4           Ankylosis or dislocation
  ------------- ------------------------- ----------- -------------------------

> ^a^ Fourteen joints per hand/wrist are examined: interphalangeal of
> digit I, proximal interphalangeal of digits II and V,
> metacarpo‑phalangeal of digits I and V, metacarpal of digit I,
> scaphoid, distal radius, and ulna. Note: Maximum raw score of both
> hands is 98, which is normalized to 100.
>
> ^b^ Thirteen joints per hand/wrist are examined: interphalangeal of
> digit I, proximal interphalangeal of digits II and V,
> metacarpo‑phalangeal of digits I and V, combination of carpometacarpal
> of digits III and V, combination of capitate, scaphoid lunate, and
> radiocarpal joint. Note: Maximum raw score of both hands is 104, which
> is normalized to 100.

#### 24-week Larsen and Modified Sharp Results

Figure 4-19 displays the 24-week radiographic results for the
prespecified Larsen score and the modified Sharp total score. Results of
the Larsen scoring of joint radiographs did not yield a statistically
significant result for any of the individual anakinra dose groups.
However, visual trends favoring anakinra were evident with a
statistically significant difference observed when all anakinra doses
were combined, and compared with placebo, p = 0.03. The results for the
modified Sharp total score yielded similar improvements, however,
statistically significant differences were observed for each of the
individual anakinra dose groups, as well as the combined anakinra doses,
when compared with placebo. Results for each of the sub-scales for the
modified Sharp score, JSN and ES (Figure 4-19) demonstrate a pattern
similar to that seen with the total score. On average, after 24 weeks of
treatment, anakinra subjects experienced reductions in disease
progression of 40% or more compared with placebo subjects.

Figure 4‑19. Radiographic Scores Change From Baseline at Week 24

![](media/image26.wmf){width="4.925694444444445in" height="3.0in"}

Modified Sharp Score

Sub-Scales

![](media/image27.wmf){width="4.925694444444445in" height="3.0in"}

P-values compare each anakinra dose group and the all anakinra group to
placebo.

Pairwise p-values are uncorrected nominal p-values from an Analysis of
Variance model.

#### Monotherapy Study (0560) and Extension Study (0564): 48-Week Radiographic Data

Upon completion of the 24-week, double-blind, placebo-controlled phase
of the Monotherapy Study (0560), subjects were eligible to continue
anakinra treatment by enrolling into extension study 0564, which
followed subjects for an additional 48 weeks for efficacy assessments.
Subjects who received placebo in the Monotherapy Study (0560) were
randomized to receive 1 of 3 anakinra doses (30 mg, 75 mg, or 150 mg) in
study 0564, and anakinra-treated subjects continued on the anakinra dose
that they were randomly assigned at entry into the Monotherapy Study
(0560), (see Figure 4-20). All subjects and investigators remained
blinded to the identity of their previous treatment in the Monotherapy
Study (0560), and also to the anakinra dose they were receiving in study
0564. For subjects participating in both studies 0560 and 0564,
radiographs were available for up to 48 weeks.

Figure 4‑. Schema for ![](media/image28.wmf){width="5.695833333333334in"
height="3.9930555555555554in"}Studies 0560 and 0564

Although the study design did not include a placebo control for a full
year, the cohort of placebo subjects crossing over from the Monotherapy
Study (0560) to receive active treatment in extension study 0564 could
be considered a scientifically valid 48-week control group under the
null hypothesis that anakinra is no more effective than placebo.
Assuming anakinra was effective in retarding radiographic disease
progression, the comparison of 48 weeks of anakinra therapy against a
placebo control group that received anakinra for half the treatment
period may be viewed as conservative and biased against detecting a true
anakinra effect. Any significant difference between these groups would
then be evidence of the efficacy of anakinra over the 48-week period and
would suggest that the true effect of long-term treatment with anakinra
was probably greater than observed. To test this hypothesis, a repeated
measures mixed model analysis of variance was used that included all
observed data for subjects with a baseline and ≥ 1 post baseline Larsen
or modified Sharp score.

Figure 4-21 displays the 24- and 48-week changes from baseline for all
subjects as they were originally randomized in the Monotherapy Study
(0560). Because previous anakinra effects on radiographic disease
progression were generally found to be independent of dose, the 3
anakinra dose groups were combined to increase statistical power and
simplify graphical displays.

Although significant differences between the anakinra and placebo groups
were not observed in the Larsen score at 48 weeks, significant
reductions in the progression of structural damage were seen after 48
weeks of anakinra therapy relative to placebo, as measured by the
modified Sharp total score (TS) (p = 0.015) and the ES (p = 0.006), with
a trend approaching statistical significance in JSN (p = 0.084). The
adjusted mean change in TS was almost twice as high for placebo subjects
(3.81) as for anakinra‑treated subjects (2.12). A similar difference was
evident for progression of JSN (1.53 vs 0.89) and ES (2.03 vs 1.15).

For the Larsen score, the 48-week results for each anakinra dose group
revealed numerical improvements relative to placebo; although none of
these differences reached statistical significance. The 48-week
differences observed for the modified Sharp score also resulted in
clinical improvements for each anakinra dose group, with statistical
significance most notable at the 75 mg and 150 mg dose groups for the
TS, and for all individual anakinra dose groups for the ES.

Consistent with the 24-week results in the previous section that used a
One-way Analysis of Variance model, the Repeated-Measures Mixed Model
Analysis employed here also showed significant anakinra treatment
effects as early as 24 weeks in the Larsen score and all 3 Sharp
endpoints: TS, JSN, and ES (p = 0.001, 0.002 and 0.047, respectively).

In summary, despite the conservative bias of this analysis against
anakinra, the results are consistent with previous analyses
demonstrating that anakinra acts as early as 24 weeks to retard
structural damage in RA, and its effects are clinically and
statistically significant through 48 weeks of treatment. Further, if the
48-week Larsen and modified Sharp scores for the placebo group in this
mixed model analysis were attenuated because of anakinra treatment
during the second 24 weeks, then these results constitute a conservative
estimate of the true effects of anakinra in the reduction of
radiographic progression.

Figure 4‑21. Radiographic Scores Change From Baseline

![](media/image29.wmf){width="4.988888888888889in"
height="3.029861111111111in"}

Modified Sharp Score

Sub-Scales

![](media/image30.wmf){width="4.988888888888889in"
height="3.029861111111111in"}

Note: Nominal p-values compare the all anakinra group to placebo based
on a repeated measures mixed model Analysis of Variance.

Note: Due to missing baseline covariates adjusted in the repeated
measures mixed model, 9 and 7 subjects were excluded from the analysis
for the Larsen and modified Sharp scores, respectively.

### Summary of Efficacy

The effectiveness of anakinra in the reduction of signs and symptoms of
RA has been independently demonstrated in 3 separate placebo-controlled
trials. Following the positive results observed in the Monotherapy Study
(0560) and the MTX Combination Study (960180), the effects of anakinra
were prospectively confirmed at a dose of 100 mg/day in the Confirmatory
Efficacy Study (990145), representing data from over 500 RA subjects.
The results across these 3 trials are remarkably consistent and robust.
Whether as a monotherapy (study 0560), or in combination with MTX
(studies 960180 and 990145), subjects treated with anakinra achieve both
clinically and statistically meaningful improvements in the signs and
symptoms of RA compared to control subjects. After 24 weeks of treatment
with anakinra, approximately 40% of subjects achieved improvements of
20% or more in the ACR composite score (ACR~20~). The improvements seen
with anakinra treatment occurred rapidly and were sustained throughout
the 24-week treatment period. Additionally, anakinra subjects were more
than twice as likely as placebo subjects to achieve greater magnitudes
of improvement, including improvements of 50% and 70% or more (ACR~50~
and ACR~70~) responses. Findings for the individual ACR components were
consistent with the positive effects observed for the ACR composite
score.

Sensitivity analyses revealed that the effects were not the result of
potential unblinding due to ISRs or due to subject dropout rates. An
important finding is that the results from each of the sensitivity
analyses conducted were consistent from trial to trial, providing strong
support for the overall conclusion that anakinra is an effective
treatment for the reduction in signs and symptoms of RA.

The Low Dose Monotherapy Study (960182), conducted to explore the
efficacy of anakinra at doses of 30 mg or less, failed to show efficacy,
and provided support for utilization of a higher dose in treatment of
subjects with RA.

Beyond the effects observed for signs and symptoms, the radiographic
data from the Larsen and Sharp scores examined in the Monotherapy Study
(0560) and its extension (0564), provide clinical evidence consistent
with the biologic rationale suggesting anakinra may be an effective
agent in the reduction of radiographic disease progression. These
radiographic results provide additional support for the role of anakinra
in the treatment of RA.

Figure 4‑22. Proportion of Subjects Responding by ACR~20~ at Week 24
Studies 0560, 960180, and 990145 Non-responder Imputation for Subjects
Receiving at Least 1 Dose of Study Drug

![](media/image31.wmf){width="3.327777777777778in"
height="2.495833333333333in"}

![](media/image32.wmf){width="3.327777777777778in"
height="2.495833333333333in"}

![](media/image33.wmf){width="3.327777777777778in"
height="2.495833333333333in"}

/stat/il1ra/subresp/analysis/brdgdoc/statfiles/graphs/g_acr20.doc
(generated 31JAN2001)

## Clinical Data - Safety 

### Introduction

The anakinra development program for RA includes dose ranging and
frequency trials, clinical pharmacology studies, randomized
placebo-controlled trials and long term extension studies (Figure 1-1).
The 5 randomized, placebo-controlled studies provide data on the safety
of anakinra as a monotherapy (0560 and 960182), in combination with MTX
(960180 and 990145), and multiple DMARD combination therapy (990757). An
open-label, single-arm trial exploring the use of anakinra in subjects
receiving etanercept therapy (study 20000125) was recently concluded and
the results from that trial are also summarized separately.

Rheumatoid arthritis therapies have historically been associated with a
variety of adverse events including infections, bone marrow suppression
and hepatotoxicity. Therefore, events in these categories and the
analysis of relevant laboratory findings are discussed in more detail.

The safety analysis and discussion focuses on the 5 randomized,
double-blind, placebo-controlled trials (Table 4-16) as these permit
direct comparison to a control group for up to 24 weeks. To describe the
longer term adverse event profile, additional safety analyses were
conducted across all RA clinical trials including the long-term
extension trials. After a brief discussion of the methodological
approach for the safety analyses, the overall exposure to anakinra in RA
subjects is reviewed, followed by a discussion of the results.

Table 4‑16. Number of Subjects Treated In All Anakinra RA Studies

+---+-------------------------------------+---------+---------+--------+
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| S |                                     |         |         |        |
| t |                                     |         |         |        |
| u |                                     |         |         |        |
| d |                                     |         |         |        |
| y |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     | **Ana   | **Pl    | **T    |
|   |                                     | kinra** | acebo** | otal** |
+---+-------------------------------------+---------+---------+--------+
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| R |                                     |         |         |        |
| a |                                     |         |         |        |
| n |                                     |         |         |        |
| d |                                     |         |         |        |
| o |                                     |         |         |        |
| m |                                     |         |         |        |
| i |                                     |         |         |        |
| z |                                     |         |         |        |
| e |                                     |         |         |        |
| d |                                     |         |         |        |
| P |                                     |         |         |        |
| l |                                     |         |         |        |
| a |                                     |         |         |        |
| c |                                     |         |         |        |
| e |                                     |         |         |        |
| b |                                     |         |         |        |
| o |                                     |         |         |        |
| - |                                     |         |         |        |
| c |                                     |         |         |        |
| o |                                     |         |         |        |
| n |                                     |         |         |        |
| t |                                     |         |         |        |
| r |                                     |         |         |        |
| o |                                     |         |         |        |
| l |                                     |         |         |        |
| l |                                     |         |         |        |
| e |                                     |         |         |        |
| d |                                     |         |         |        |
| S |                                     |         |         |        |
| t |                                     |         |         |        |
| u |                                     |         |         |        |
| d |                                     |         |         |        |
| i |                                     |         |         |        |
| e |                                     |         |         |        |
| s |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Monotherapy Study (0560)            | 351     | 121     | 472    |
+---+-------------------------------------+---------+---------+--------+
|   | Low Dose Monotherapy Study (960182) | 111     | 30      | 141    |
+---+-------------------------------------+---------+---------+--------+
|   | MTX Combination Study (960180)      | 345     | 74      | 419    |
+---+-------------------------------------+---------+---------+--------+
|   | Confirmatory Efficacy Study         | 250     | 251     | 501    |
|   | (990145)                            |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Safety Study (990757)               | 1116    | 283     | 1399   |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
| * |                                     | ***     | **      | ***2   |
| * |                                     | 2173*** | *759*** | 932*** |
| * |                                     |         |         |        |
| T |                                     |         |         |        |
| o |                                     |         |         |        |
| t |                                     |         |         |        |
| a |                                     |         |         |        |
| l |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     | **Ana   | **Pl    | **T    |
|   |                                     | kinra** | acebo** | otal** |
+---+-------------------------------------+---------+---------+--------+
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| S |                                     |         |         |        |
| u |                                     |         |         |        |
| p |                                     |         |         |        |
| p |                                     |         |         |        |
| o |                                     |         |         |        |
| r |                                     |         |         |        |
| t |                                     |         |         |        |
| i |                                     |         |         |        |
| v |                                     |         |         |        |
| e |                                     |         |         |        |
| R |                                     |         |         |        |
| A |                                     |         |         |        |
| S |                                     |         |         |        |
| t |                                     |         |         |        |
| u |                                     |         |         |        |
| d |                                     |         |         |        |
| i |                                     |         |         |        |
| e |                                     |         |         |        |
| s |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Dose and Frequency Study (0505)     | 175     | NA      | 175    |
+---+-------------------------------------+---------+---------+--------+
|   | Continuous Infusion Study (980220)  | 18      | 3       | 21     |
+---+-------------------------------------+---------+---------+--------+
| * |                                     | **      | ***3*** | ***    |
| * |                                     | *193*** |         | 196*** |
| * |                                     |         |         |        |
| T |                                     |         |         |        |
| o |                                     |         |         |        |
| t |                                     |         |         |        |
| a |                                     |         |         |        |
| l |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
| * |                                     | **      | **A     | **T    |
| * |                                     | Placebo | nakinra | otal** |
| I |                                     | to\     | to      |        |
| n |                                     | Ana     | Ana     |        |
| E |                                     | kinra** | kinra** |        |
| x |                                     |         |         |        |
| t |                                     |         |         |        |
| e |                                     |         |         |        |
| n |                                     |         |         |        |
| s |                                     |         |         |        |
| i |                                     |         |         |        |
| o |                                     |         |         |        |
| n |                                     |         |         |        |
| S |                                     |         |         |        |
| t |                                     |         |         |        |
| u |                                     |         |         |        |
| d |                                     |         |         |        |
| i |                                     |         |         |        |
| e |                                     |         |         |        |
| s |                                     |         |         |        |
| , |                                     |         |         |        |
| s |                                     |         |         |        |
| u |                                     |         |         |        |
| b |                                     |         |         |        |
| j |                                     |         |         |        |
| e |                                     |         |         |        |
| c |                                     |         |         |        |
| t |                                     |         |         |        |
| s |                                     |         |         |        |
| c |                                     |         |         |        |
| r |                                     |         |         |        |
| o |                                     |         |         |        |
| s |                                     |         |         |        |
| s |                                     |         |         |        |
| - |                                     |         |         |        |
| o |                                     |         |         |        |
| v |                                     |         |         |        |
| e |                                     |         |         |        |
| r |                                     |         |         |        |
| f |                                     |         |         |        |
| r |                                     |         |         |        |
| o |                                     |         |         |        |
| m |                                     |         |         |        |
| : |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| L |                                     |         |         |        |
| o |                                     |         |         |        |
| n |                                     |         |         |        |
| g |                                     |         |         |        |
| - |                                     |         |         |        |
| t |                                     |         |         |        |
| e |                                     |         |         |        |
| r |                                     |         |         |        |
| m |                                     |         |         |        |
| S |                                     |         |         |        |
| t |                                     |         |         |        |
| u |                                     |         |         |        |
| d |                                     |         |         |        |
| i |                                     |         |         |        |
| e |                                     |         |         |        |
| s |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Multi-Dose PK Extension Study       | NA      | 11      | 11     |
|   | (0502E)^a^                          |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Dose and Frequency Extension Study  | NA      | 148     | 148    |
|   | (0512)                              |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Monotherapy Extension Studies\      | 76      | 233     | 309    |
|   | (0564, 0546E1, 0564E2, 0564E3)      |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | MTX Combination Extension Study     | 57      | 252     | 309    |
|   | (960181)                            |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Low Dose Monotherapy Extension      | 26      | 86      | 112    |
|   | Study (970102)                      |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Continuous Infusion Extension Study | 6^b^    | 18      | 24     |
|   | (980220)                            |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
| * |                                     | **      | **      | ***    |
| * |                                     | *165*** | *748*** | 913*** |
| * |                                     |         |         |        |
| T |                                     |         |         |        |
| o |                                     |         |         |        |
| t |                                     |         |         |        |
| a |                                     |         |         |        |
| l |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     | **Ana   | **Pl    | **T    |
|   |                                     | kinra** | acebo** | otal** |
+---+-------------------------------------+---------+---------+--------+
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| C |                                     |         |         |        |
| l |                                     |         |         |        |
| i |                                     |         |         |        |
| n |                                     |         |         |        |
| i |                                     |         |         |        |
| c |                                     |         |         |        |
| a |                                     |         |         |        |
| l |                                     |         |         |        |
| P |                                     |         |         |        |
| h |                                     |         |         |        |
| a |                                     |         |         |        |
| r |                                     |         |         |        |
| m |                                     |         |         |        |
| a |                                     |         |         |        |
| c |                                     |         |         |        |
| o |                                     |         |         |        |
| l |                                     |         |         |        |
| o |                                     |         |         |        |
| g |                                     |         |         |        |
| y |                                     |         |         |        |
| S |                                     |         |         |        |
| t |                                     |         |         |        |
| u |                                     |         |         |        |
| d |                                     |         |         |        |
| i |                                     |         |         |        |
| e |                                     |         |         |        |
| s |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| ^ |                                     |         |         |        |
| a |                                     |         |         |        |
| ^ |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   | Single-Dose PK Study (0501)         | 20      | 5       | 25     |
+---+-------------------------------------+---------+---------+--------+
|   | Multi-Dose PK Study (0502)          | 15      | NA      | 15     |
+---+-------------------------------------+---------+---------+--------+
|   | 4-Day Continuous Infusion PK Study  | 40      | 10      | 50     |
|   | (970189)                            |         |         |        |
+---+-------------------------------------+---------+---------+--------+
|   |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
| * |                                     | *       | *       | **     |
| * |                                     | **75*** | **15*** | *90*** |
| * |                                     |         |         |        |
| T |                                     |         |         |        |
| o |                                     |         |         |        |
| t |                                     |         |         |        |
| a |                                     |         |         |        |
| l |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
| * |                                     |         |         |        |
+---+-------------------------------------+---------+---------+--------+
| ^ |                                     |         |         |        |
| a |                                     |         |         |        |
| ^ |                                     |         |         |        |
| N |                                     |         |         |        |
| o |                                     |         |         |        |
| t |                                     |         |         |        |
| i |                                     |         |         |        |
| n |                                     |         |         |        |
| c |                                     |         |         |        |
| l |                                     |         |         |        |
| u |                                     |         |         |        |
| d |                                     |         |         |        |
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+---+-------------------------------------+---------+---------+--------+
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+---+-------------------------------------+---------+---------+--------+

#### Methodology

##### Analytic Groups

As noted previously, the primary safety analysis focuses on the 5
randomized, placebo-controlled trials (Table 4-16) which comprise 91% of
all study subjects. To support the proposed dose of 100 mg/day, the
safety data from subjects exposed to anakinra in these trials were
categorized by dose as below, at, or above 100 mg/day, and are compared
to placebo.

In addition to the analysis of these 5 placebo-controlled trials,
adverse event data for subjects exposed to anakinra across all RA
clinical trials, including the long-term extension trials, are provided.
The group of all RA clinical trials includes the anakinra exposure
contributed by the double-blind portion of the 5 placebo-controlled
studies as well as the anakinra exposure contributed by the Supportive
RA Studies, and Long-term Studies, see Table 4-16. The Clinical
Pharmacology Studies are not included due to limited exposure, but
results are described where relevant. In essence, 2 analytic groups have
been established for the assessment of safety: 1) the combined data from
the 24-week double-blind portions in the 5 randomized,
placebo-controlled trials, and 2) the safety data for subjects exposed
to anakinra in all RA clinical trials including those in the long term
extension studies.

Since the 5 randomized, controlled studies include a placebo control
group for up to 24 weeks (except the Low Dose Monotherapy Study,
960182), adverse event data are presented as the crude subject incidence
of events, ie, the percentage of subjects having at least 1 event.
Adjustments for exposure have not been made since exposure to study drug
is similar among the 5 trials (see Section 4.5.2), and adjusting for
exposure does not affect the overall conclusions.

As discussed earlier, the Confirmatory Efficacy Study (990145) remains
blinded, and only a small number of Amgen personnel not directly
involved in study conduct have been unblinded for the purposes of data
analysis. In order to protect the blind and maintain the integrity of
the study, safety data from this study will be presented in aggregate
form, that is, unblinded to the treatment group, but blinded at the
individual subject level. As such, treatment assignments for individual
subjects in this study are not presented.

For the long-term assessment of safety (all RA clinical trials), the
exposure-adjusted adverse event rates across anakinra groups are
presented, thus taking into account varying study durations across
trials, including subjects exposed to anakinra for as long as 5 years.
Also, event rates, rather than subject incidences are analyzed in these
long-term analyses to avoid censure of events occurring in patients who
experienced similar events early on in their treatment.
Exposure-adjusted adverse event rates are calculated as the total number
of treatment-emergent adverse events in each category, divided by the
total time on study drug, and expressed as the event rate per
patient-year (or 100 patient-years).

####### Clinical Pharmacology Studies {#clinical-pharmacology-studies .FlushLeftBold .unnumbered}

Three clinical pharmacology studies (0501, 0502 and 970189) in RA
subjects (and 1 extension, 0502E) were excluded from the analyses
because they have a limited number of subjects (Table 4-16) and subject
exposure, and because of inherent methodological differences in such
pharmacology studies. For completeness, however, events of note in these
studies are discussed where appropriate in this briefing package.

##### Adverse Events -- Definitions

-   Adverse events and serious adverse events (SAEs) as defined in 21
    CFR 312.32(a) were collected by staff at the study site using
    study-specific case report forms. Severity and relatedness were
    judged by the principal investigators.

-   Injection Site Reactions (ISRs) were collected as part of the
    general adverse event reporting procedures. Preferred terms such as
    injection site erythema, pruritus, rash, and inflammation are
    collectively referred to as 'ISRs' (Table 4-20).

-   Infectious Episodes in earlier RA studies were categorized using a
    list of events considered infectious in nature based on data review
    by Amgen personnel. In the Confirmatory Efficacy Study (990145) and
    the Safety Study (990757), separate case report forms were
    designated for collection of events considered by the principal
    investigator to be of an infectious nature. Microbiologic
    confirmation of these events was not collected.

### Exposure for Safety Analyses

#### Randomized, Placebo-controlled Studies

The total exposure (patient-years), mean and median subject exposure for
the 5 randomized placebo-controlled RA studies are shown in Table 4-17.
As expected, the median subject exposure for the placebo-controlled
phases in these trials is 24 weeks. Therefore, the comparison of crude
(ie, unadjusted for exposure) subject incidence rates across these dose
categories is appropriate.

Table 4‑17. Exposure by Dose Group for Placebo-controlled Studies

+-------------------------+--------+--------+-------+-------+-------+
|                         |        | An     |       |       |       |
|                         |        | akinra |       |       |       |
|                         |        | (mg)   |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
|                         | P      | \< 100 | 100   | \>    | All   |
|                         | lacebo |        |       | 100   |       |
+-------------------------+--------+--------+-------+-------+-------+
|                         | (N =   | (N =   | (N =  | (N =  | (N =  |
|                         | 759)   | 610)   | 1367) | 196)  | 2173) |
+-------------------------+--------+--------+-------+-------+-------+
|                         |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
| Total exposure          | 296.2  | 214.7  | 559.3 | 70.9  | 845.0 |
| (patient-years)         |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
|                         |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
| Mean patient exposure   | 20.4   | 18.4   | 21.3  | 18.9  | 20.3  |
| (wks)                   |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
|                         |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
| Median patient exposure | 24.0   | 23.9   | 24.4  | 24.0  | 24.1  |
| (wks)                   |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
| Includes studies 0560,  |        |        |       |       |       |
| 960180, 960182, 990145, |        |        |       |       |       |
| and 990757              |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
| N = Number of           |        |        |       |       |       |
| randomized subjects who |        |        |       |       |       |
| received at least 1     |        |        |       |       |       |
| dose of study drug      |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
| Year conversion: 1 year |        |        |       |       |       |
| = 365.25 days           |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+
| /stat                   |        |        |       |       |       |
| /il1ra/fda_brfpkg/analy |        |        |       |       |       |
| sis/safety/statfiles/ta |        |        |       |       |       |
| bles/t_exposure_rct.sas |        |        |       |       |       |
|                         |        |        |       |       |       |
| Output:                 |        |        |       |       |       |
| t_exposure_rct.rtf      |        |        |       |       |       |
| (generated 29JUN2001)   |        |        |       |       |       |
+-------------------------+--------+--------+-------+-------+-------+

#### All RA Studies

For all RA trials (including the 5 randomized, placebo-controlled
studies), total exposure (patient-years), mean and median subject
exposure are shown in Table 4-18. These exposure data include exposure
beyond the initial placebo-controlled periods (up to 24 weeks) for those
placebo-controlled trials with extensions. The follow-up period includes
clinical data submitted in the BLA (cutoff date August 31, 1999), and
the 24-week data from the Confirmatory Efficacy Study (990145) and the
large Safety Study (990757). Some subjects are included in more than one
group because in the extension studies those subjects were assigned to a
different treatment group than that assigned in the original trial; eg,
placebo in the original study, and 150 mg anakinra in the extension
study. It is important to note that the total patient-years of exposure
to anakinra (1872.9) is 6-fold greater than the total patient-years of
exposure to placebo (296.7). Hence it is to be expected that the
reported numbers of adverse events, unrelated to study drug, would be
greater among anakinra subjects.

Table 4‑18. Exposure by Dose Group for All RA Studies

+------------------------+--------+--------+--------+--------+--------+
|                        |        | An     |        |        |        |
|                        |        | akinra |        |        |        |
|                        |        | (mg)   |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
|                        | P      | \< 100 | 100    | \> 100 | All^a^ |
|                        | lacebo |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
|                        | (N =   | (N =   | (N =   | (N =   | (N =   |
|                        | 762)   | 980)   | 1367)  | 428)   | 2531)  |
+------------------------+--------+--------+--------+--------+--------+
| Total exposure         | 296.7  | 993.5  | 559.6  | 319.8  | 1872.9 |
| (patient-years)        |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
| Mean patient exposure  | 20.3   | 52.9   | 21.4   | 39.0   | 38.6   |
| (wks)                  |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
| Median patient         | 24.0   | 41.0   | 24.4   | 20.0   | 25.0   |
| exposure (wks)         |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
| Includes studies 0505, |        |        |        |        |        |
| 0512, 0560, 0564,      |        |        |        |        |        |
| 0564E1, 0564E2,        |        |        |        |        |        |
| 0564E3, 960180,        |        |        |        |        |        |
| 960181, 960182,        |        |        |        |        |        |
| 970102, 980220,        |        |        |        |        |        |
| 990145, and 990757     |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
| N = Number of          |        |        |        |        |        |
| randomized subjects    |        |        |        |        |        |
| who received at least  |        |        |        |        |        |
| 1 dose of study drug   |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
| Year conversion: 1     |        |        |        |        |        |
| year = 365.25 days     |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
| ^a^Some subjects may   |        |        |        |        |        |
| be included in         |        |        |        |        |        |
| multiple dose groups   |        |        |        |        |        |
| (original trial and    |        |        |        |        |        |
| extension)             |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+
| /sta                   |        |        |        |        |        |
| t/il1ra/fda_brfpkg/ana |        |        |        |        |        |
| lysis/safety/statfiles |        |        |        |        |        |
| /tables/t_exposure.sas |        |        |        |        |        |
|                        |        |        |        |        |        |
| Output: t_exposure.rtf |        |        |        |        |        |
| (generated 29JUN2001)  |        |        |        |        |        |
+------------------------+--------+--------+--------+--------+--------+

### Adverse Events

#### Randomized, Placebo-controlled Trials

Table 4-19 presents the subject incidence of adverse events occurring in
≥ 5% of the anakinra group for the 5 randomized, placebo-controlled
studies. Adverse events occurring in ≥ 5% of placebo subjects but \< 5%
of anakinra subjects are not shown. The most frequently reported adverse
event in the anakinra groups is injection site reactions (ISRs).
Although the overall incidence of adverse events is slightly higher in
anakinra subjects compared with placebo and there appears to be a dose
response, this effect is no longer evident when adverse events
associated with ISRs are excluded (Table 4-44).

The majority of ISRs in the anakinra group (95.3%) were mild or moderate
in nature. ISRs are discussed further in Section 4.5.3.2.

Events coded 'Arthritis-Rheumatoid' (ie, worsening of RA) were more
common in placebo than anakinra subjects. Headaches were slightly more
common in anakinra groups than in the placebo (Appendix 4-9).

All other most frequently observed adverse events occurred at a
relatively similar incidence among groups.

Table 4‑19. Subject Incidence of Treatment-Emergent Adverse Events for
Placebo-controlled Studies (≥ 5% in\
All Anakinra Group)

  ------------- -------------------- --------- -------- -- ---------- -------- -- ------- -------- -- ------ -------- -- ------- -------- --
                                                           Anakinra                                                                       
                                                           (mg)                                                                           

                                     Placebo               \< 100                 100                 \> 100             All              

  Preferred                          (N = 759)             (N = 610)              (N =                (N =               (N =             
  Term - n (%)                                                                    1367)               196)               2173)            

  Any                                645       (85.0)      538        (88.2)      1254    (91.7)      190    (96.9)      1982    (91.2)   

                                                                                                                                          

  Injection                          204       (26.9)      281        (46.1)      973     (71.2)      145    (74.0)      1399    (64.4)   
  Site Reaction                                                                                                                           

  Arthritis                          205       (27.0)      86         (14.1)      261     (19.1)      25     (12.8)      372     (17.1)   
  Rheumatoid                                                                                                                              

  URI                                105       (13.8)      63         (10.3)      189     (13.8)      23     (11.7)      275     (12.7)   

  Headache                           60        (7.9)       65         (10.7)      168     (12.3)      22     (11.2)      255     (11.7)   

  Nausea                             49        (6.5)       40         (6.6)       115     (8.4)       11     (5.6)       166     (7.6)    

  Diarrhea                           43        (5.7)       37         (6.1)       97      (7.1)       11     (5.6)       145     (6.7)    

  Sinusitis                          43        (5.7)       25         (4.1)       98      (7.2)       8      (4.1)       131     (6.0)    

  Arthralgia                         56        (7.4)       40         (6.6)       76      (5.6)       11     (5.6)       127     (5.8)    

  Flu-Like                           39        (5.1)       29         (4.8)       82      (6.0)       14     (7.1)       125     (5.8)    
  Symptoms                                                                                                                                

  Pain                               32        (4.2)       35         (5.7)       73      (5.3)       14     (7.1)       122     (5.6)    
  Abdominal                                                                                                                               

  Includes                                                                                                                                
  studies 0560,                                                                                                                           
  960180,                                                                                                                                 
  960182,                                                                                                                                 
  990145, and                                                                                                                             
  990757                                                                                                                                  

  Injection                                                                                                                               
  Site Reaction                                                                                                                           
  includes all                                                                                                                            
  preferred                                                                                                                               
  terms under                                                                                                                             
  the                                                                                                                                     
  Application                                                                                                                             
  Site body                                                                                                                               
  system.                                                                                                                                 

  N = Number of                                                                                                                           
  randomized                                                                                                                              
  subjects who                                                                                                                            
  received at                                                                                                                             
  least 1 dose                                                                                                                            
  of study drug                                                                                                                           

  n = Number of                                                                                                                           
  subjects                                                                                                                                
  reporting at                                                                                                                            
  least 1                                                                                                                                 
  occurrence of                                                                                                                           
  an adverse                                                                                                                              
  event                                                                                                                                   

  \% = (n/N) x                                                                                                                            
  100                                                                                                                                     
  ------------- -------------------- --------- -------- -- ---------- -------- -- ------- -------- -- ------ -------- -- ------- -------- --

#### Injection Site Reactions (ISRs)

In the 5 randomized, placebo-controlled studies, the incidence of ISRs
is higher in anakinra groups (64.4%) compared with placebo (26.9%; see
Table 4-19).

The incidence of ISRs increases with higher anakinra doses. In the
majority of cases in the anakinra group (95.3%), these events were mild
or moderate. In the placebo controlled studies, 5.6% anakinra and 1.3%
placebo subjects withdrew as a result of ISRs (Table 4-27). ISRs were
most frequently characterized by localized erythema, pruritus, rash,
and/or pain (Table 4-20). Those ISRs reported by investigators as severe
consisted of erythematous, indurated, and/or painful lesions. Events
such as pain and ecchymosis may be associated more with injection site
trauma than a true reaction to anakinra. This is evident from the
relatively high incidence of these 2 events in the placebo group (12.3
and 12.4%, respectively). One subject, receiving 100 mg anakinra,
reportedly had skin necrosis at an injection site. This occurred on
study day 13 and resolved on study day 77. The adverse event was not
considered serious by the investigator, was reported to be of moderate
intensity, and the subject was not withdrawn from study due to this
event.

The cumulative probability curves for the time to first ISR of subjects
receiving 100 mg anakinra compared with placebo are shown in Figure 4-23
(combined data from the large Safety Study \[990757\] and the
Confirmatory Efficacy Study \[990145\]). The estimated median time to
first ISR in subjects who experienced at least 1 event is 11 days for
anakinra subjects and 3 days for placebo subjects. Subjects who do not
experience an ISR within 4 weeks of initiation of therapy are highly
unlikely to experience an ISR subsequently.

Table 4‑20. Injection Site Reactions by Preferred Term for
Placebo-controlled Studies

  ------------------- -------------------- --------- -------- -- ---------- -------- -- ------- -------- -- ------ -------- -- ------- -------- --
                                                                 Anakinra                                                                       
                                                                 (mg)                                                                           

                                           Placebo               \< 100                 100                 \> 100             All              

  Preferred Term - n                       (N = 759)             (N = 610)              (N =                (N =               (N =             
  (%)                                                                                   1367)               196)               2173)            

                                                                                                                                                

  Any                                      204       (26.9)      281        (46.1)      973     (71.2)      145    (74.0)      1399    (64.4)   

                                                                                                                                                

  ISR - Erythema                           35        (4.6)       150        (24.6)      505     (36.9)      90     (45.9)      745     (34.3)   

  ISR - Pruritus                           14        (1.8)       60         (9.8)       412     (30.1)      36     (18.4)      508     (23.4)   

  ISR - Rash                               10        (1.3)       61         (10.0)      315     (23.0)      32     (16.3)      408     (18.8)   

  ISR - Pain                               93        (12.3)      37         (6.1)       250     (18.3)      10     (5.1)       297     (13.7)   

  ISR - Ecchymosis                         94        (12.4)      59         (9.7)       200     (14.6)      15     (7.7)       274     (12.6)   

  ISR - Inflammation                       3         (0.4)       6          (1.0)       137     (10.0)      7      (3.6)       150     (6.9)    

  ISR - Urticaria                          2         (0.3)       16         (2.6)       116     (8.5)       6      (3.1)       138     (6.4)    

  ISR - Edema                              8         (1.1)       24         (3.9)       63      (4.6)       15     (7.7)       102     (4.7)    

  ISR - Not Specified                      4         (0.5)       29         (4.8)       47      (3.4)       19     (9.7)       95      (4.4)    

  ISR - Pruritic                           0         (0.0)       6          (1.0)       13      (1.0)       1      (0.5)       20      (0.9)    
  Erythema                                                                                                                                      

  ISR - Hemorrhage                         8         (1.1)       4          (0.7)       10      (0.7)       2      (1.0)       16      (0.7)    

  ISR - Hematoma                           1         (0.1)       5          (0.8)       3       (0.2)       5      (2.6)       13      (0.6)    

  ISR - Paresthesia                        6         (0.8)       8          (1.3)       1       (0.1)       3      (1.5)       12      (0.6)    

  ISR - Mass                               1         (0.1)       3          (0.5)       2       (0.1)       0      (0.0)       5       (0.2)    

  ISR - Pigmentation                       0         (0.0)       0          (0.0)       2       (0.1)       0      (0.0)       2       (0.1)    
  Abnormal                                                                                                                                      

  ISR - Skin                               0         (0.0)       0          (0.0)       2       (0.1)       0      (0.0)       2       (0.1)    
  Discoloration                                                                                                                                 

  ISR - Skin                               0         (0.0)       2          (0.3)       0       (0.0)       0      (0.0)       2       (0.1)    
  Hyperpigmentation                                                                                                                             

  ISR - Infection                          0         (0.0)       0          (0.0)       1       (0.1)       0      (0.0)       1       (0.0)    

  ISR - Necrosis                           0         (0.0)       0          (0.0)       1       (0.1)       0      (0.0)       1       (0.0)    

  Includes studies                                                                                                                              
  0560, 960180,                                                                                                                                 
  960182, 990145, and                                                                                                                           
  990757                                                                                                                                        

  N = Number of                                                                                                                                 
  randomized subjects                                                                                                                           
  who received at                                                                                                                               
  least 1 dose of                                                                                                                               
  study drug                                                                                                                                    

  n = Number of                                                                                                                                 
  subjects reporting                                                                                                                            
  at least 1                                                                                                                                    
  occurrence of an                                                                                                                              
  adverse event                                                                                                                                 

  \% = (n/N) x 100                                                                                                                              

                                                                                                                                                
  ------------------- -------------------- --------- -------- -- ---------- -------- -- ------- -------- -- ------ -------- -- ------- -------- --

Figure 4‑23. Time to First Injection Site Reaction for Studies 990145
and 990757

![](media/image34.wmf){width="8.0in" height="5.1090277777777775in"}

### Serious Adverse Events

Table 4-21 summarizes all SAEs occurring in at least 0.2% of subjects in
the All Anakinra group. Serious Adverse events occurring in ≥ 0.2% of
placebo subjects but\
\< 0.2% anakinra subjects are not shown. A complete summary of all SAEs
is provided in Appendix 4-10.

Overall, the most common SAE was worsening of RA (term "Arthritis
Rheumatoid"). This occurred most commonly in the placebo group and the
\< 100 mg anakinra group. Among the 3 anakinra groups, the incidence was
inversely related to dose. Most adverse events designated as 'serious'
were associated with hospitalization and thus met the regulatory
definition of a serious adverse event (Section 4.5.1.1.2).

The next most common SAE, pneumonia, is discussed in Section 4.5.6.2.

The other events in Table 4-21 occurred rarely and do not appear to be
associated with anakinra therapy.

Table 4‑21. Serious Adverse Events (Crude Subject Incidence) by
Preferred Term for Placebo-controlled Studies\
(Occurring in ≥ 0.2% of All Anakinra Subjects)

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 28%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 4%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</td>
</tr>
<tr class="even">
<td colspan="2">Any</td>
<td>49</td>
<td>(6.5)</td>
<td></td>
<td>51</td>
<td>(8.4)</td>
<td></td>
<td>97</td>
<td>(7.1)</td>
<td></td>
<td>24</td>
<td>(12.2)</td>
<td></td>
<td>172</td>
<td>(7.9)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Arthritis Rheumatoid</td>
<td>12</td>
<td>(1.6)</td>
<td></td>
<td>10</td>
<td>(1.6)</td>
<td></td>
<td>10</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>21</td>
<td>(1.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pneumonia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>11</td>
<td>(0.5)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pain Abdominal</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>5</td>
<td>(0.8)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>9</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Arthralgia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>6</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Abdominal Hernia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Dyspnea</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cardiac Failure</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hemorrhage GI</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Nausea</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Vomiting</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Fracture</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Muscle Weakness</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Tendon Disorder</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="even">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="odd">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="even">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td colspan="17"></td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_pterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

#### All RA Studies

Table 4-22 shows the exposure-adjusted SAE incidence rates for all RA
clinical trials. For comparison, the exposure-adjusted SAE incidence
rates for the double-blind periods for the 5 randomized,
placebo-controlled studies are also provided. SAEs are reported as the
number of events per 100 patient-years of exposure to study drug. This
table includes exposure-adjusted events that occurred at a rate of ≥
0.45 events per 100 patients-years in the placebo-controlled anakinra
group (N=2173). Comparing the 2 anakinra columns below, similar event
rates for each of the SAEs listed are observed, indicating that the
incidence of an SAE does not increase with longer exposure to anakinra.

Table 4‑22. SAEs (Exposure-adjusted Event Incidence) by Preferred Term
for Placebo-controlled and All Studies (≥ 0.45 events/100-patient-years
in Placebo-controlled Anakinra)

+-------------------------+------+-------+-----+-------+---+----+------+
|                         | Pl   |       |     |       |   | A  |      |
|                         | aceb |       |     |       |   | ll |      |
|                         | o-co |       |     |       |   | St |      |
|                         | ntro |       |     |       |   | ud |      |
|                         | lled |       |     |       |   | ie |      |
|                         | St   |       |     |       |   | s^ |      |
|                         | udie |       |     |       |   | b^ |      |
|                         | s^a^ |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
|                         | Pla  |       | An  |       |   | An |      |
|                         | cebo |       | aki |       |   | ak |      |
|                         |      |       | nra |       |   | in |      |
|                         |      |       |     |       |   | ra |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| n (events per 100       | (N = |       | (N  |       |   | (N |      |
| patient years)          | 759) |       | =   |       |   | =  |      |
|                         |      |       | 21  |       |   | 2  |      |
|                         |      |       | 73) |       |   | 53 |      |
|                         |      |       |     |       |   | 1) |      |
+-------------------------+------+-------+-----+-------+---+----+------+
|                         |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| Any                     | 72   | (2    | 288 | (3    |   | 6  | (32  |
|                         |      | 4.31) |     | 4.08) |   | 16 | .89) |
+-------------------------+------+-------+-----+-------+---+----+------+
|                         |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| Arthritis Rheumatoid    | 12   | (     | 22  | (     |   | 45 | (2   |
|                         |      | 4.05) |     | 2.60) |   |    | .40) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Pneumonia               | 0    | (     | 12  | (     |   | 18 | (0   |
|                         |      | 0.00) |     | 1.42) |   |    | .96) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Pain Abdominal          | 2    | (     | 9   | (     |   | 20 | (1   |
|                         |      | 0.68) |     | 1.07) |   |    | .07) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Arthralgia              | 1    | (     | 6   | (     |   | 8  | (0   |
|                         |      | 0.34) |     | 0.71) |   |    | .43) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Abdominal Hernia        | 0    | (     | 5   | (     |   | 5  | (0   |
|                         |      | 0.00) |     | 0.59) |   |    | .27) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Dyspnea                 | 0    | (     | 5   | (     |   | 9  | (0   |
|                         |      | 0.00) |     | 0.59) |   |    | .48) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Fracture                | 3    | (     | 5   | (     |   | 8  | (0   |
|                         |      | 1.01) |     | 0.59) |   |    | .43) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Bursitis                | 0    | (     | 4   | (     |   | 7  | (0   |
|                         |      | 0.00) |     | 0.47) |   |    | .37) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Cardiac Failure         | 1    | (     | 4   | (     |   | 6  | (0   |
|                         |      | 0.34) |     | 0.47) |   |    | .32) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Hemorrhage GI           | 0    | (     | 4   | (     |   | 13 | (0   |
|                         |      | 0.00) |     | 0.47) |   |    | .69) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Muscle Weakness         | 0    | (     | 4   | (     |   | 4  | (0   |
|                         |      | 0.00) |     | 0.47) |   |    | .21) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Nausea                  | 1    | (     | 4   | (     |   | 7  | (0   |
|                         |      | 0.34) |     | 0.47) |   |    | .37) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Tendon Disorder         | 1    | (     | 4   | (     |   | 9  | (0   |
|                         |      | 0.34) |     | 0.47) |   |    | .48) |
+-------------------------+------+-------+-----+-------+---+----+------+
| Vomiting                | 1    | (     | 4   | (     |   | 9  | (0   |
|                         |      | 0.34) |     | 0.47) |   |    | .48) |
+-------------------------+------+-------+-----+-------+---+----+------+
| ^a^Includes studies     |      |       |     |       |   |    |      |
| 0560, 960180, 960182,   |      |       |     |       |   |    |      |
| 990145, and 990757      |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| ^b^Includes studies     |      |       |     |       |   |    |      |
| 0505, 0512, 0560, 0564, |      |       |     |       |   |    |      |
| 0564E1, 0564E2, 0564E3, |      |       |     |       |   |    |      |
| 960180, 960181, 960182, |      |       |     |       |   |    |      |
| 970102, 980220, 990145, |      |       |     |       |   |    |      |
| and 990757              |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
|                         |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| N = Number of           |      |       |     |       |   |    |      |
| randomized subjects who |      |       |     |       |   |    |      |
| received at least 1     |      |       |     |       |   |    |      |
| dose of study drug      |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| n = Number of adverse   |      |       |     |       |   |    |      |
| events                  |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| Patient year of         |      |       |     |       |   |    |      |
| exposure is the         |      |       |     |       |   |    |      |
| duration between the    |      |       |     |       |   |    |      |
| first dose date and the |      |       |     |       |   |    |      |
| last dose date.         |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+
| /stat/il                |      |       |     |       |   |    |      |
| 1ra/fda_brfpkg/analysis |      |       |     |       |   |    |      |
| /safety/statfiles/table |      |       |     |       |   |    |      |
| s/t_ae_event_rctall.sas |      |       |     |       |   |    |      |
|                         |      |       |     |       |   |    |      |
| Output:                 |      |       |     |       |   |    |      |
| t_ae_eve                |      |       |     |       |   |    |      |
| nt_rctall_ser_pterm.rtf |      |       |     |       |   |    |      |
| (generated 29JUN2001)   |      |       |     |       |   |    |      |
+-------------------------+------+-------+-----+-------+---+----+------+

#### Clinical Pharmacology RA Studies 

Serious adverse events from clinical pharmacology studies not included
in the exposure-adjusted event rate analyses (studies 0501, 0502, 0502E,
and 970189) are described below. These events do not alter the overall
assessment of SAEs.

-   Studies 0501 and 0502: no SAEs were reported.

-   Study 970189: 1 SAE (pleuritis with back and chest pain, shortness
    of breath, and pleurisy), was reported in a subject receiving
    2.0 mg/kg/day anakinra by continuous SC infusion (deemed unrelated).
    No cardiovascular pathology was identified.

-   Study 0502E: 1 SAE (hives, edema of the upper lip, and pruritus) was
    reported in a subject in study 0502E leading to subject withdrawal
    from study drug. A 61- year old male subject received a cumulative
    dose of 32 mg/kg anakinra in the initial protocol (0502) over 75
    days, 46 days of which comprised a washout period between treatment
    stages (during which no drug was administered). The subject
    developed hives, edema of the upper lip, and pruritus the day after
    he received his first injection of 100 mg anakinra (study 0502E day
    1). These symptoms were treated with 1 injection of 40 mg
    methylprednisolone acetate (Depo-Medrol) IM and 25 mg oral
    hydroxyzine hydrochloride (Atarax) every 6 hours. The hives and
    edema resolved 5 days after onset. The pruritus resolved 6 days
    after it appeared. Anakinra was discontinued on study day 5 (0502E)
    after the subject had received a total of 2 injections of 100 mg
    anakinra. The investigator judged the hives and edema to be severe,
    while the pruritus was considered to be of moderate severity. This
    subject had no known history of allergy and was not concurrently
    exposed to other new drugs. These events were all assessed by the
    investigator as being probably related to study drug.

The anakinra safety database for RA studies was reviewed for serious
hypersensitivity reactions coded to allergic reaction, anaphylactoid
reaction, anaphylaxis, angioedema, and systemic hypersensitivity
reaction. Only 1 other case reported as possibly related to anakinra
meet these criteria:

-   Study 960180: A 62-year-old female subject with a history of RA
    began receiving daily SC injections of anakinra. Approximately 90
    days after the start of study drug, the subject developed diffuse
    urticaria and possible angioedema. The subject was treated in the
    emergency room and subsequently hospitalized 4 weeks later. The
    subject received IV methylprednisolone for 3 days. The angioedema
    and urticaria resolved after 4 days, and the subject was discharged
    on a tapering dose of oral steroids. The test article was continued
    unchanged. The subject's medical and surgical history includes
    allergies to "sulfa", iodine, codeine, and prochlorperazine. The
    investigator considered the development of possible angioedema and
    diffuse urticaria to be unrelated to study drug.

Serious systemic hypersensitivity reactions were rarely observed and
were not assessed as life-threatening. One subject continued therapy
with no reoccurrences, and in the other subject the event subsided after
withdrawal of study drug.

### Deaths

In the 24-week double-blind period of the 5 randomized,
placebo-controlled studies, there have been 6 (0.3%) deaths reported for
anakinra and 1 (0.1%) for placebo (Table 4-44). One death from study
990145 was not included in these calculations since the study is still
blinded.

As shown in Table 4-24, Table 4-25, Table 4-26, to date, a total of 29
deaths have been reported, including the 23 deaths among subjects known
to have received anakinra, 2 subjects known to have received placebo,
and 4 subjects (study 990145) whose treatment assignment remains
blinded. Narratives are provided where appropriate in . summarizes the
cause of death among subjects known to have received anakinra. All
subjects who died were ≥ 51 years old, and the majority had pre-existing
illnesses other than RA, or predisposing comorbidities relevant to the
cause of death. The most common cause of death was cardiovascular
disease. Cancer and infection are discussed in Section 4.5.7 and Section
4.5.6, respectively.

Deaths reported in the BLA (December 1999) and the subsequent amendment
containing 24-week data from the large Safety Study (990757) and the
Confirmatory Efficacy Study (990145) are summarized below. For
completeness, additional reports of deaths as of January 2001 not
included in the BLA or subsequent amendment are summarized separately.
See Appendix 4-11.

**Table 4‑23. Summary of Cause of Death Among Subjects\
Known to Have Received Anakinra**

  ---------------------------------------------------------- ------------
  **Cause of Death**                                         **N**

  Cardiovascular disease                                     9

  Cancer                                                     5

  Infection                                                  4

  Chronic lung disease                                       1

  Suicide                                                    1

  Asthma                                                     1

  Gastrointestinal hemorrhage                                1

  Unknown                                                    1
  ---------------------------------------------------------- ------------

> Source: bs-dg-causeofdeath_11JUL01

In summary, evaluation of deaths in the anakinra RA studies fails to
establish an overall relationship between treatment with anakinra and
events that resulted in death.

#### Deaths Reported in the BLA

Of the 29 deaths, a total of 13 deaths were reported in the BLA (total
of 1321 subjects): 5 occurred on study, and 8 deaths were reported after
subjects withdrew from study drug (Table 4-24). All 13 subjects were on
anakinra treatment, 2 deaths were considered by the investigators to be
related to anakinra (both subjects received 30 mg/day; Monotherapy Study
0560 and Monotherapy Extension Study 0564E1). The exposure in this
anakinra group (1310 patient-years) is significantly greater than in
this placebo group (76 patient-years), hence it is to be expected that
more deaths would occur in the anakinra group, in the absence of a
relationship to study drug. Four deaths among the anakinra-treated
subjects occurred \> 3 months after the last dose of study drug and were
reported as unrelated to anakinra by the investigators. These deaths are
excluded from the analyses in Table 4-44 and Table 4-45. See
Appendix 4-11.

#### Deaths Reported in BLA Amendment (Studies 990757 and 990145)

As discussed earlier, data from 501 subjects in the Confirmatory
Efficacy Study (990145) and 1399 subjects in the Safety Study (990757)
were submitted as part of the Complete Response to questions received
from CBER. Among the subjects for whom data were included in this
amendment, there were 6 deaths, of which 1 was a placebo subject (study
990757); 1 death in study 990145 remains blinded. Of the 6 deaths, 1 was
considered related to anakinra (100 mg/day; study 990757). See
Appendix 4-11.

#### Deaths Reported in Ongoing Studies

In the ongoing clinical trials there have been 10 additional deaths
reported. Three occurred in the Confirmatory Efficacy Study (990145) and
treatment assignment remains blinded. Of the remaining 7 deaths, 1
occurred in a placebo subject (study 990757), and 1 was reported as
related to anakinra (2 mg/kg; MTX Combination Extension Study 960181).
See Appendix 4-11..

Table 4‑24. By-Subject Listing of Deaths Submitted in BLA

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 23%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 28%" />
<col style="width: 4%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Study</td>
<td>Age</td>
<td>Sex</td>
<td>Relevant medical history</td>
<td>Daily Dose</td>
<td>Days on study drug</td>
<td colspan="2">Death<br />
on study/<br />
post-study</td>
<td>Cause of death</td>
<td>Rel<sup>a</sup></td>
</tr>
<tr class="even">
<td>0560</td>
<td>75</td>
<td>Male</td>
<td>Ten-year history of COPD</td>
<td>75 mg</td>
<td>126</td>
<td colspan="2">&gt; 3 mo post</td>
<td>Respiratory infection/failure</td>
<td>No</td>
</tr>
<tr class="odd">
<td></td>
<td>73</td>
<td>Female</td>
<td>Transient ischemic attacks</td>
<td>150 mg</td>
<td>71</td>
<td colspan="2">&lt; 30 d post</td>
<td>Cerebrovascular accident and hemiparesis</td>
<td>No</td>
</tr>
<tr class="even">
<td></td>
<td>55</td>
<td>Male</td>
<td>Smoking</td>
<td>30 mg</td>
<td>168</td>
<td colspan="2">3 mo post</td>
<td>Small cell lung cancer</td>
<td>Yes</td>
</tr>
<tr class="odd">
<td>0564</td>
<td>68</td>
<td>Male</td>
<td>Ischemic heart disease, angina</td>
<td>75 mg</td>
<td>454</td>
<td colspan="2">On study</td>
<td>Ventricular fibrillation</td>
<td>No</td>
</tr>
<tr class="even">
<td></td>
<td>67</td>
<td>Male</td>
<td>None</td>
<td>75 mg</td>
<td>532</td>
<td colspan="2">3 mo post</td>
<td>Gastric carcinoma</td>
<td>No</td>
</tr>
<tr class="odd">
<td>0564E1</td>
<td>88</td>
<td>Female</td>
<td>Diverticulitis</td>
<td>150 mg</td>
<td>636</td>
<td colspan="2">&gt; 30 d post</td>
<td>Myocardial ischemia secondary to coronary artery disease</td>
<td>No</td>
</tr>
<tr class="even">
<td></td>
<td>72</td>
<td>Female</td>
<td>Hypertension, renal insufficiency, pneumonia</td>
<td>30 mg</td>
<td>776</td>
<td colspan="2">&lt; 30 d post</td>
<td>Endocarditis, circulatory failure</td>
<td>Yes</td>
</tr>
<tr class="odd">
<td>0564E2</td>
<td>79</td>
<td>Male</td>
<td>None</td>
<td>75 mg</td>
<td>942</td>
<td>&gt; 30 d post</td>
<td colspan="2">Pancreatic neoplasm</td>
<td>No</td>
</tr>
<tr class="even">
<td>960181</td>
<td>70</td>
<td>Female</td>
<td>Angina, hypertension, MI, CABG</td>
<td>0.4 mg/kg</td>
<td>151</td>
<td colspan="2">&lt; 30 d post</td>
<td>Myocardial infarction</td>
<td>No</td>
</tr>
<tr class="odd">
<td></td>
<td>76</td>
<td>Female</td>
<td>Bowel obstruction, hypertension</td>
<td>2.0 mg/kg</td>
<td>531</td>
<td colspan="2">On study</td>
<td>Unknown; possibly cardiopulmonary failure</td>
<td>No</td>
</tr>
<tr class="even">
<td>0512</td>
<td>51</td>
<td>Female</td>
<td>UTI, hypertension, cerebral infarct</td>
<td>70 mg</td>
<td>124</td>
<td colspan="2">On study</td>
<td>Pneumonia and sepsis</td>
<td>No</td>
</tr>
<tr class="odd">
<td></td>
<td>76</td>
<td>Female</td>
<td>Transient ischemic attacks, phlebitis, uterine cancer</td>
<td>70 mg 3x/wk</td>
<td>105</td>
<td colspan="2">On study</td>
<td>Cerebrovascular accident</td>
<td>No</td>
</tr>
<tr class="even">
<td></td>
<td>58</td>
<td>Male</td>
<td>DM, gout</td>
<td>70 mg 1x/wk</td>
<td>57</td>
<td colspan="2">On study</td>
<td>Cardiac arrest</td>
<td>No</td>
</tr>
<tr class="odd">
<td colspan="10"><p><sup>a</sup> Causality per investigator: No = not
related or unlikely; Yes = possibly, probably, or definitely related to
study drug.</p>
<p>DM = diabetes mellitus, MI = myocardial infarction, CABG = coronary
artery bypass graft, UTI = urinary tract infection</p></td>
</tr>
<tr class="even">
<td colspan="10">Output:
/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/listings/t_death.doc
(generated 05JUL2001)</td>
</tr>
</tbody>
</table>

Table 4‑25. By-Subject Listing of Deaths Reported in the BLA Amendment
(Studies 990757 and 990145)

<table style="width:100%;">
<colgroup>
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 23%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 28%" />
<col style="width: 4%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Study</td>
<td>Age</td>
<td>Sex</td>
<td>Relevant medical history</td>
<td>Daily Dose</td>
<td>Days on study drug</td>
<td>Death<br />
on study/<br />
post-study</td>
<td colspan="2">Cause of death</td>
<td>Rel<sup>a</sup></td>
</tr>
<tr class="even">
<td>990757</td>
<td>60</td>
<td>Female</td>
<td>Interstitial lung disease (possibly related to MTX), DM</td>
<td>100 mg</td>
<td>134</td>
<td colspan="2">On study</td>
<td>Pulmonary fibrosis and Respiratory failure</td>
<td>Yes</td>
</tr>
<tr class="odd">
<td></td>
<td>67</td>
<td>Female</td>
<td>Panic attacks and depression</td>
<td>100 mg</td>
<td>56</td>
<td colspan="2">On study</td>
<td>Suicide</td>
<td>No</td>
</tr>
<tr class="even">
<td></td>
<td>67</td>
<td>Male</td>
<td>Melanoma</td>
<td>100 mg</td>
<td>105</td>
<td colspan="2">On study</td>
<td>Cerebral and pulmonary metastatic melanoma</td>
<td>No</td>
</tr>
<tr class="odd">
<td></td>
<td>68</td>
<td>Male</td>
<td>DM, hypertension</td>
<td>Placebo</td>
<td>53</td>
<td colspan="2">On study</td>
<td>Myocardial infarction</td>
<td>No</td>
</tr>
<tr class="even">
<td></td>
<td>61</td>
<td>Female</td>
<td>Esophagitis, gastric ulcers, gastritis</td>
<td>100 mg</td>
<td>~30</td>
<td colspan="2">&lt; 30 d post</td>
<td>Upper gastrointestinal hemorrhage</td>
<td>No</td>
</tr>
<tr class="odd">
<td>990145</td>
<td>80</td>
<td>Male</td>
<td>Chronic interstitial lung disease</td>
<td>Blinded</td>
<td>87</td>
<td colspan="2">&gt; 30 d post</td>
<td>Progressive interstitial lung disease with fibrosis</td>
<td>No</td>
</tr>
<tr class="even">
<td colspan="10"><p><sup>a</sup> Causality per investigator: No = not
related or unlikely; Yes = possibly, probably, or definitely related to
study drug.</p>
<p>DM = diabetes mellitus, MI = myocardial infarction, CABG = coronary
artery bypass graft, UTI = urinary tract infection</p></td>
</tr>
<tr class="odd">
<td colspan="10">Output:
/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/listings/t_death.doc
(generated 05JUL2001)</td>
</tr>
</tbody>
</table>

Table 4‑26. By-Subject Listing of Deaths Reported in Ongoing Studies

+----+---+----+----------------+-----+---+------+-------------------+---+
| S  | A | S  | Relevant       | Da  | D | De   | Cause of death    | R |
| tu | g | ex | medical        | ily | a | ath\ |                   | e |
| dy | e |    | history        | d   | y | on   |                   | l |
|    |   |    |                | ose | s | stu  |                   | ^ |
|    |   |    |                |     | o | dy/\ |                   | a |
|    |   |    |                |     | n | po   |                   | ^ |
|    |   |    |                |     | s | st-s |                   |   |
|    |   |    |                |     | t | tudy |                   |   |
|    |   |    |                |     | u |      |                   |   |
|    |   |    |                |     | d |      |                   |   |
|    |   |    |                |     | y |      |                   |   |
|    |   |    |                |     | d |      |                   |   |
|    |   |    |                |     | r |      |                   |   |
|    |   |    |                |     | u |      |                   |   |
|    |   |    |                |     | g |      |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
| 96 | 5 | Fe | Smoker for 32  | 2   | 1 | On   | Gastric carcinoma | N |
| 01 | 1 | ma | years; anemia  | mg  | 0 | s    | with brain and    | o |
| 81 |   | le |                | /kg | 5 | tudy | thigh metastases  |   |
|    |   |    |                |     | 6 |      |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
|    | 7 | Fe | None           | 2   | 8 | On   | Cardiac arrest    | N |
|    | 5 | ma |                | mg  | 2 | s    | with sepsis       | o |
|    |   | le |                | /kg | 4 | tudy | following         |   |
|    |   |    |                |     |   |      | c                 |   |
|    |   |    |                |     |   |      | holecysto-colonic |   |
|    |   |    |                |     |   |      | fistula surgery   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
|    | 7 | Ma | CHF, MI        | 2   | 8 | \<   | Sepsis from       | Y |
|    | 0 | le |                | mg  | 1 | 30 d | abdominal wall    | e |
|    |   |    |                | /kg | 8 | post | abscess           | s |
+----+---+----+----------------+-----+---+------+-------------------+---+
| 99 | 7 | Fe | Asthma         | B   | 8 | On   | Unknown; died in  | N |
| 01 | 1 | ma |                | lin | 8 | s    | sleep after       | o |
| 45 |   | le |                | ded |   | tudy | flu-like          |   |
|    |   |    |                |     |   |      | symptoms,         |   |
|    |   |    |                |     |   |      | diarrhea, and     |   |
|    |   |    |                |     |   |      | fever             |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
|    | 7 | Ma | DM, COPD       | B   | 5 | On   | Cardiac failure   | N |
|    | 4 | le |                | lin | 7 | s    |                   | o |
|    |   |    |                | ded |   | tudy |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
|    | 5 | Ma | Hypertension,  | B   | 1 | On   | MI                | N |
|    | 3 | le | smoking,       | lin | 8 | s    |                   | o |
|    |   |    | h              | ded | 5 | tudy |                   |   |
|    |   |    | yperlipidemia, |     |   |      |                   |   |
|    |   |    | obesity, tooth |     |   |      |                   |   |
|    |   |    | abscess        |     |   |      |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
| 99 | 5 | Ma | Atrial         | Pl  | 1 | On   | Cardiac arrest    | N |
| 07 | 1 | le | fibrillation,  | ace | 7 | s    | and CVA           | o |
| 57 |   |    | alcohol abuse, | bo\ | 1 | tudy |                   |   |
|    |   |    | CHF, aortic    | 100 | \ |      |                   |   |
|    |   |    | regurgitation, | mg  | 1 |      |                   |   |
|    |   |    | aspiration     |     | 5 |      |                   |   |
|    |   |    | pneumonia,     |     | 7 |      |                   |   |
|    |   |    | seizures       |     |   |      |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
|    | 5 | Ma | Asthma,        | 100 | 2 | \>   | Asthma            | N |
|    | 5 | le | hypertension   | mg  | 5 | 30 d |                   | o |
|    |   |    |                |     | 9 | post |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
|    | 7 | Fe | CAD, CHF,      | 100 | 2 | On   | Ventricular       | N |
|    | 6 | ma | hypertension,  | mg  | 7 | s    | failure and CAD   | o |
|    |   | le | MI             |     | 1 | tudy |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
|    | 7 | Fe | COPD, Herpes   | P   | 1 | \>   | Respiratory       | N |
|    | 0 | ma | zoster         | lac | 5 | 30 d | failure due to    | o |
|    |   | le |                | ebo | 6 | post | pulmonary         |   |
|    |   |    |                |     |   |      | metastatic        |   |
|    |   |    |                |     |   |      | squamous cell     |   |
|    |   |    |                |     |   |      | carcinoma         |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
| ^  |   |    |                |     |   |      |                   |   |
| a^ |   |    |                |     |   |      |                   |   |
| C  |   |    |                |     |   |      |                   |   |
| au |   |    |                |     |   |      |                   |   |
| sa |   |    |                |     |   |      |                   |   |
| li |   |    |                |     |   |      |                   |   |
| ty |   |    |                |     |   |      |                   |   |
| p  |   |    |                |     |   |      |                   |   |
| er |   |    |                |     |   |      |                   |   |
| i  |   |    |                |     |   |      |                   |   |
| nv |   |    |                |     |   |      |                   |   |
| es |   |    |                |     |   |      |                   |   |
| ti |   |    |                |     |   |      |                   |   |
| ga |   |    |                |     |   |      |                   |   |
| to |   |    |                |     |   |      |                   |   |
| r: |   |    |                |     |   |      |                   |   |
| No |   |    |                |     |   |      |                   |   |
| =  |   |    |                |     |   |      |                   |   |
| n  |   |    |                |     |   |      |                   |   |
| ot |   |    |                |     |   |      |                   |   |
| r  |   |    |                |     |   |      |                   |   |
| el |   |    |                |     |   |      |                   |   |
| at |   |    |                |     |   |      |                   |   |
| ed |   |    |                |     |   |      |                   |   |
| or |   |    |                |     |   |      |                   |   |
| u  |   |    |                |     |   |      |                   |   |
| nl |   |    |                |     |   |      |                   |   |
| ik |   |    |                |     |   |      |                   |   |
| el |   |    |                |     |   |      |                   |   |
| y; |   |    |                |     |   |      |                   |   |
| Y  |   |    |                |     |   |      |                   |   |
| es |   |    |                |     |   |      |                   |   |
| =  |   |    |                |     |   |      |                   |   |
| p  |   |    |                |     |   |      |                   |   |
| os |   |    |                |     |   |      |                   |   |
| si |   |    |                |     |   |      |                   |   |
| bl |   |    |                |     |   |      |                   |   |
| y, |   |    |                |     |   |      |                   |   |
| p  |   |    |                |     |   |      |                   |   |
| ro |   |    |                |     |   |      |                   |   |
| ba |   |    |                |     |   |      |                   |   |
| bl |   |    |                |     |   |      |                   |   |
| y, |   |    |                |     |   |      |                   |   |
| or |   |    |                |     |   |      |                   |   |
| de |   |    |                |     |   |      |                   |   |
| fi |   |    |                |     |   |      |                   |   |
| ni |   |    |                |     |   |      |                   |   |
| te |   |    |                |     |   |      |                   |   |
| ly |   |    |                |     |   |      |                   |   |
| r  |   |    |                |     |   |      |                   |   |
| el |   |    |                |     |   |      |                   |   |
| at |   |    |                |     |   |      |                   |   |
| ed |   |    |                |     |   |      |                   |   |
| to |   |    |                |     |   |      |                   |   |
| s  |   |    |                |     |   |      |                   |   |
| tu |   |    |                |     |   |      |                   |   |
| dy |   |    |                |     |   |      |                   |   |
| d  |   |    |                |     |   |      |                   |   |
| ru |   |    |                |     |   |      |                   |   |
| g. |   |    |                |     |   |      |                   |   |
|    |   |    |                |     |   |      |                   |   |
| DM |   |    |                |     |   |      |                   |   |
| =  |   |    |                |     |   |      |                   |   |
| di |   |    |                |     |   |      |                   |   |
| ab |   |    |                |     |   |      |                   |   |
| et |   |    |                |     |   |      |                   |   |
| es |   |    |                |     |   |      |                   |   |
| m  |   |    |                |     |   |      |                   |   |
| el |   |    |                |     |   |      |                   |   |
| li |   |    |                |     |   |      |                   |   |
| tu |   |    |                |     |   |      |                   |   |
| s, |   |    |                |     |   |      |                   |   |
| MI |   |    |                |     |   |      |                   |   |
| =  |   |    |                |     |   |      |                   |   |
| my |   |    |                |     |   |      |                   |   |
| oc |   |    |                |     |   |      |                   |   |
| ar |   |    |                |     |   |      |                   |   |
| di |   |    |                |     |   |      |                   |   |
| al |   |    |                |     |   |      |                   |   |
| i  |   |    |                |     |   |      |                   |   |
| nf |   |    |                |     |   |      |                   |   |
| ar |   |    |                |     |   |      |                   |   |
| ct |   |    |                |     |   |      |                   |   |
| io |   |    |                |     |   |      |                   |   |
| n, |   |    |                |     |   |      |                   |   |
| CA |   |    |                |     |   |      |                   |   |
| BG |   |    |                |     |   |      |                   |   |
| =  |   |    |                |     |   |      |                   |   |
| co |   |    |                |     |   |      |                   |   |
| ro |   |    |                |     |   |      |                   |   |
| na |   |    |                |     |   |      |                   |   |
| ry |   |    |                |     |   |      |                   |   |
| ar |   |    |                |     |   |      |                   |   |
| te |   |    |                |     |   |      |                   |   |
| ry |   |    |                |     |   |      |                   |   |
| by |   |    |                |     |   |      |                   |   |
| pa |   |    |                |     |   |      |                   |   |
| ss |   |    |                |     |   |      |                   |   |
| gr |   |    |                |     |   |      |                   |   |
| af |   |    |                |     |   |      |                   |   |
| t, |   |    |                |     |   |      |                   |   |
| U  |   |    |                |     |   |      |                   |   |
| TI |   |    |                |     |   |      |                   |   |
| =  |   |    |                |     |   |      |                   |   |
| u  |   |    |                |     |   |      |                   |   |
| ri |   |    |                |     |   |      |                   |   |
| na |   |    |                |     |   |      |                   |   |
| ry |   |    |                |     |   |      |                   |   |
| t  |   |    |                |     |   |      |                   |   |
| ra |   |    |                |     |   |      |                   |   |
| ct |   |    |                |     |   |      |                   |   |
| i  |   |    |                |     |   |      |                   |   |
| nf |   |    |                |     |   |      |                   |   |
| ec |   |    |                |     |   |      |                   |   |
| ti |   |    |                |     |   |      |                   |   |
| on |   |    |                |     |   |      |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+
| O  |   |    |                |     |   |      |                   |   |
| ut |   |    |                |     |   |      |                   |   |
| pu |   |    |                |     |   |      |                   |   |
| t: |   |    |                |     |   |      |                   |   |
| /  |   |    |                |     |   |      |                   |   |
| st |   |    |                |     |   |      |                   |   |
| at |   |    |                |     |   |      |                   |   |
| /i |   |    |                |     |   |      |                   |   |
| l1 |   |    |                |     |   |      |                   |   |
| ra |   |    |                |     |   |      |                   |   |
| /f |   |    |                |     |   |      |                   |   |
| da |   |    |                |     |   |      |                   |   |
| _b |   |    |                |     |   |      |                   |   |
| rf |   |    |                |     |   |      |                   |   |
| pk |   |    |                |     |   |      |                   |   |
| g/ |   |    |                |     |   |      |                   |   |
| an |   |    |                |     |   |      |                   |   |
| al |   |    |                |     |   |      |                   |   |
| ys |   |    |                |     |   |      |                   |   |
| is |   |    |                |     |   |      |                   |   |
| /s |   |    |                |     |   |      |                   |   |
| af |   |    |                |     |   |      |                   |   |
| et |   |    |                |     |   |      |                   |   |
| y/ |   |    |                |     |   |      |                   |   |
| st |   |    |                |     |   |      |                   |   |
| at |   |    |                |     |   |      |                   |   |
| fi |   |    |                |     |   |      |                   |   |
| le |   |    |                |     |   |      |                   |   |
| s/ |   |    |                |     |   |      |                   |   |
| li |   |    |                |     |   |      |                   |   |
| st |   |    |                |     |   |      |                   |   |
| in |   |    |                |     |   |      |                   |   |
| gs |   |    |                |     |   |      |                   |   |
| /t |   |    |                |     |   |      |                   |   |
| _d |   |    |                |     |   |      |                   |   |
| ea |   |    |                |     |   |      |                   |   |
| th |   |    |                |     |   |      |                   |   |
| .d |   |    |                |     |   |      |                   |   |
| oc |   |    |                |     |   |      |                   |   |
| (g |   |    |                |     |   |      |                   |   |
| en |   |    |                |     |   |      |                   |   |
| er |   |    |                |     |   |      |                   |   |
| at |   |    |                |     |   |      |                   |   |
| ed |   |    |                |     |   |      |                   |   |
| 10 |   |    |                |     |   |      |                   |   |
| JU |   |    |                |     |   |      |                   |   |
| L2 |   |    |                |     |   |      |                   |   |
| 00 |   |    |                |     |   |      |                   |   |
| 1) |   |    |                |     |   |      |                   |   |
+----+---+----+----------------+-----+---+------+-------------------+---+

#### Withdrawals Due To Adverse Events

##### Randomized, Placebo-controlled Studies

Table 4-27, summarizes the most common events (≥ 0.2% in the 'all
anakinra' group) that resulted in withdrawal in subjects participating
in the 5 randomized, placebo-controlled studies. Withdrawals occurring
in ≥ 0.2% of placebo subjects but \< 0.2% of anakinra subjects are not
shown. A summary including all withdrawals due to adverse events is
provided in Appendix 4-12.

Overall, the incidence of withdrawals due to adverse events is slightly
higher in the 100 mg and \> 100 mg anakinra groups compared with placebo
and \< 100 mg groups. The most common reasons for withdrawal are ISRs
(5.6% in the 'all anakinra' group compared with 1.3% in the placebo
group) and worsening of RA (2.9% for 'all anakinra' and 6.2% for placebo
subjects, when the preferred terms "arthritis rheumatoid" and
"arthralgia" are combined). ISRs are discussed in Section 4.5.3.2.

Protocol-mandated withdrawals due to leukopenia or granulocytopenia
occurred as follows: 1 in the \< 100 mg and 3 in the \> 100 mg anakinra
groups. Only 1 subject, a 63-year old man in the MTX Combination Study
(960180), had Grade 3 neutropenia (Table 4-41). In the later studies
(990757 and 990145) where such withdrawals were not mandated, only 1 of
1366 subjects (0.07%) had a Grade 3 neutropenia (ANC of 0.79 x 10^9^/L).
Significant cases of neutropenia are discussed further in Section
4.5.10.

In summary, analysis of patient withdrawals supports the conclusion that
anakinra was generally well tolerated.

Table 4‑27. Subject Incidence of Treatment-Emergent Adverse Events
Leading to Withdrawal for Placebo-controlled\
Studies Occurring in ≥ 0.2% of All Anakinra Group

  ------------------ -------------------- --------- -------- -- ---------- ------- -- ------- -------- -- ------ -------- -- ------- -------- --
                                                                Anakinra                                                                      
                                                                (mg)                                                                          

                                          Placebo               \< 100                100                 \> 100             All              

  Preferred Term - n                      (N = 759)             (N = 610)             (N =                (N =               (N =             
  (%)                                                                                 1367)               196)               2173)            

  Any                                     88        (11.6)      58         (9.5)      186     (13.6)      36     (18.4)      280     (12.9)   

                                                                                                                                              

  Injection Site                          10        (1.3)       8          (1.3)      100     (7.3)       14     (7.1)       122     (5.6)    
  Reaction                                                                                                                                    

  Arthritis                               46        (6.1)       28         (4.6)      22      (1.6)       7      (3.6)       57      (2.6)    
  Rheumatoid                                                                                                                                  

  Headache                                4         (0.5)       0          (0.0)      8       (0.6)       0      (0.0)       8       (0.4)    

  Pain Abdominal                          3         (0.4)       1          (0.2)      7       (0.5)       0      (0.0)       8       (0.4)    

  Arthralgia                              1         (0.1)       1          (0.2)      3       (0.2)       2      (1.0)       6       (0.3)    

  Fatigue                                 1         (0.1)       0          (0.0)      5       (0.4)       1      (0.5)       6       (0.3)    

  Leukopenia                              0         (0.0)       4          (0.7)      1       (0.1)       1      (0.5)       6       (0.3)    

  Dizziness                               0         (0.0)       0          (0.0)      5       (0.4)       0      (0.0)       5       (0.2)    

  Dyspnea                                 1         (0.1)       1          (0.2)      4       (0.3)       0      (0.0)       5       (0.2)    

  Pneumonia                               0         (0.0)       2          (0.3)      3       (0.2)       0      (0.0)       5       (0.2)    

  Granulocytopenia                        0         (0.0)       1          (0.2)      0       (0.0)       3      (1.5)       4       (0.2)    

  Nausea                                  0         (0.0)       0          (0.0)      4       (0.3)       0      (0.0)       4       (0.2)    

  Includes studies                                                                                                                            
  0560, 960180,                                                                                                                               
  960182, 990145,                                                                                                                             
  and 990757                                                                                                                                  

  Injection Site                                                                                                                              
  Reaction includes                                                                                                                           
  all preferred                                                                                                                               
  terms under the                                                                                                                             
  Application Site                                                                                                                            
  body system.                                                                                                                                

  N = Number of                                                                                                                               
  randomized                                                                                                                                  
  subjects who                                                                                                                                
  received at least                                                                                                                           
  1 dose of study                                                                                                                             
  drug                                                                                                                                        

  n = Number of                                                                                                                               
  subjects reporting                                                                                                                          
  at least 1                                                                                                                                  
  occurrence of an                                                                                                                            
  adverse event                                                                                                                               

  \% = (n/N) x 100                                                                                                                            

                                                                                                                                              

                                                                                                                                              
  ------------------ -------------------- --------- -------- -- ---------- ------- -- ------- -------- -- ------ -------- -- ------- -------- --

##### Clinical Pharmacology RA Studies

Studies 0501 and 970189: no withdrawals due to adverse events were
reported.

Study 0502: 3 subjects were withdrawn due to adverse events (balanitis;
worsening of anemia; and neutropenia). The subject who withdrew due to
neutropenia had received 1 dose of 4.0 mg/kg anakinra in the first stage
of the study and 1.0 mg/kg daily in the second stage. The subject was
withdrawn 10 days after receiving study drug in stage two. The subject,
who may have had Felty syndrome, is discussed further in Section
4.5.10.1.2.

Study 0502E: 3 subjects withdrew due to adverse events (chest tightness,
fever, headache, and thyroiditis \[1\]; constant tinnitus \[1\]; hives
and edema of the upper lip \[1; see SAE discussion Section 4.5.4.2\].

### Infectious Events

#### Randomized, Placebo-controlled Studies

Analysis of infectious events is provided as descriptive statistics in
standard safety tables. In addition, the following post-hoc analyses are
provided:

1.  cumulative probability curves for time to first infection (below),

2.  corticosteroid use (Section 4.5.6.3), and

3.  predisposing comorbid conditions (Section 4.5.6.4)

Table 4-28 presents an overview of events of possible infectious nature
in the 5 randomized, placebo-controlled studies (≥ 1.0% in the 'all
anakinra' group). Overall, the incidence of any infectious event is
similar in anakinra (39.3%) compared with placebo (36.2%) subjects.
Infection of the upper respiratory tract was the most common type of
infection, experienced by 12.0% of anakinra subjects and 12.5% of
placebo subjects. There were no reported cases of tuberculosis or
opportunistic infections. A summary of all infections is provided in\
Appendix 4-13.

The cumulative probability curves for the time to first infection in
subjects receiving 100 mg anakinra compared with placebo are presented
in Figure 4-24 for studies 990145 and 990757 combined, and for each
study separately. This analysis reveals that there is no clinically
meaningful difference in time to first infection for anakinra vs
placebo-treated subjects.

Table 4‑28. Infections by Preferred Term for Placebo-controlled Studies\
(≥ 1.0% in the All Anakinra group)

  ------------------ -------------------- --------- -------- -- ---------- -------- -- ------- -------- -- ------ -------- -- ------- -------- --
                                                                Anakinra                                                                       
                                                                (mg)                                                                           

                                          Placebo               \< 100                 100                 \> 100             All              

  Preferred Term - n                      (N = 759)             (N = 610)              (N =                (N =               (N =             
  (%)                                                                                  1367)               196)               2173)            

                                                                                                                                               

  Any                                     275       (36.2)      227        (37.2)      544     (39.8)      84     (42.9)      855     (39.3)   

                                                                                                                                               

  URI                                     95        (12.5)      63         (10.3)      174     (12.7)      23     (11.7)      260     (12.0)   

  Sinusitis                               36        (4.7)       25         (4.1)       86      (6.3)       8      (4.1)       119     (5.5)    

  Flu-Like Symptoms                       35        (4.6)       29         (4.8)       74      (5.4)       14     (7.1)       117     (5.4)    

  UTI                                     37        (4.9)       23         (3.8)       62      (4.5)       10     (5.1)       95      (4.4)    

  Bronchitis                              26        (3.4)       18         (3.0)       48      (3.5)       3      (1.5)       69      (3.2)    

  Infection                               15        (2.0)       8          (1.3)       38      (2.8)       6      (3.1)       52      (2.4)    

  Fever                                   11        (1.4)       13         (2.1)       15      (1.1)       12     (6.1)       40      (1.8)    

  Moniliasis                              0         (0.0)       8          (1.7)       14      (1.4)       1      (0.7)       23      (1.4)    
  Genital^a^                                                                                                                                   

  Herpes Simplex                          9         (1.2)       10         (1.6)       14      (1.0)       1      (0.5)       25      (1.2)    

  Conjunctivitis                          10        (1.3)       8          (1.3)       11      (0.8)       3      (1.5)       22      (1.0)    

  Includes studies                                                                                                                             
  0560, 960180,                                                                                                                                
  960182, 990145,                                                                                                                              
  and 990757                                                                                                                                   

  N = Number of                                                                                                                                
  randomized                                                                                                                                   
  subjects who                                                                                                                                 
  received at least                                                                                                                            
  1 dose of study                                                                                                                              
  drug                                                                                                                                         

  n = Number of                                                                                                                                
  subjects reporting                                                                                                                           
  at least 1                                                                                                                                   
  occurrence of an                                                                                                                             
  adverse event                                                                                                                                

  \% = (n/N) x 100                                                                                                                             

  ^a^ Reproductive                                                                                                                             
  AE rates are                                                                                                                                 
  gender-specific.                                                                                                                             

                                                                                                                                               
  ------------------ -------------------- --------- -------- -- ---------- -------- -- ------- -------- -- ------ -------- -- ------- -------- --

Figure 4‑24. Time to First Infection

![](media/image35.wmf){width="8.0in" height="5.081944444444445in"}

#### Randomized, Placebo-Controlled Studies: Serious Infections

When reviewed by preferred term, there are no serious infections with an
occurrence in \> 1% of subjects (Table 4-29). Pneumonia, at a frequency
of 0.5%, was the most commonly reported serious infection in the 'all
anakinra' group (0.0% in placebo). Overall, serious infections occurred
in 1.7% of 'all anakinra' subjects compared with 0.7% in the placebo
group. None of the 8 deaths reported in the 24-week double-blind portion
of the 5 randomized, placebo-controlled studies were the result of an
infectious event. Non-infectious events appearing in Table 4-29, eg,
asthma and esophagitis, are included because they occurred with other
infectious events.

As shown in Table 4-30, the incidence of withdrawals due to infections
is 1.0% in the All Anakinra group compared with 0.8% in the placebo
group.

The subject incidence of serious infections appears to be higher at the
100 mg dose relative to placebo (1.8% vs 0.7%, respectively). This
difference in subject incidence of serious infection appears to be
driven by the Safety Study (990757; 2.1% vs 0.4%), and not the
Confirmatory Efficacy Study (990145; 0.4% vs 0.4%). Additionally,
infections judged by the investigators as severe or life-threatening
were noted among 3.1% of subjects at the 100 mg dose and 1.4% of
subjects receiving placebo. In the Safety Study (990757), 3.3% of
subjects at the 100 mg dose, and 1.1% of subjects receiving placebo
experienced severe or life-threatening infections; in the Confirmatory
Efficacy Study (990145) these events occurred in 2.0% and 1.2% of
anakinra and placebo subjects, respectively. As discussed previously,
subjects enrolled in the Safety Study (990757) differ from the other
trials due to the broad entry criteria. In study 990757, the possible
association of anakinra and the risk of infections with regard to the
use of concomitant medications and the existence of co-morbid conditions
is discussed in Section 4.5.6.3 and Section 4.5.6.4.

Table 4‑29. Subject Incidence of Serious Infections by Preferred Term
for Placebo-controlled Studies

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Any</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>7</td>
<td>(1.1)</td>
<td></td>
<td>25</td>
<td>(1.8)</td>
<td></td>
<td>4</td>
<td>(2.0)</td>
<td></td>
<td>36</td>
<td>(1.7)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pneumonia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>11</td>
<td>(0.5)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Bursitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Cellulitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Infection</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Abscess</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Bronchitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Osteomyelitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pneumonia Bacterial</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pelvic Inflammation<sup>a</sup></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Appendicitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Asthma</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Bronchopneumonia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Diarrhea</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Empyema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Esophagitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gastroenteritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Herpes Zoster</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Infection Bacterial</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Infection Respiratory Tract</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">LRI</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pleural Effusion</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pyelonephritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 1 of 2</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_ser_infect.rtf (generated 03JUL2001)</p></td>
</tr>
</tbody>
</table>

Table 4-25. Serious Infections by Preferred Term for Placebo-controlled
Studies (continued)

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">URI</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">UTI</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Cholecystitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gangrene</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 2 of 2</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_ser_infect.rtf (generated 03JUL2001)</p></td>
</tr>
</tbody>
</table>

Table 4‑30. Subject Incidence of Infectious Episodes for
Placebo-controlled Studies

<table style="width:100%;">
<colgroup>
<col style="width: 2%" />
<col style="width: 21%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Any</td>
<td>275</td>
<td>(36.2)</td>
<td></td>
<td>227</td>
<td>(37.2)</td>
<td></td>
<td>544</td>
<td>(39.8)</td>
<td></td>
<td>84</td>
<td>(42.9)</td>
<td></td>
<td>855</td>
<td>(39.3)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Severe or Life-threatening</td>
<td>11</td>
<td>(1.4)</td>
<td></td>
<td>5</td>
<td>(0.8)</td>
<td></td>
<td>42</td>
<td>(3.1)</td>
<td></td>
<td>7</td>
<td>(3.6)</td>
<td></td>
<td>54</td>
<td>(2.5)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Serious</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>7</td>
<td>(1.1)</td>
<td></td>
<td>25</td>
<td>(1.8)</td>
<td></td>
<td>4</td>
<td>(2.0)</td>
<td></td>
<td>36</td>
<td>(1.7)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Withdrawal</td>
<td>6</td>
<td>(0.8)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>16</td>
<td>(1.2)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>21</td>
<td>(1.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"></td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_sersevwd_infect.sas</p>
<p>Output: t_ae_sersevwd_infect.rtf (generated 05JUL2001)</p></td>
</tr>
</tbody>
</table>

When the terms "pneumonia", "pneumonia bacterial", and
"bronchopneumonia" are combined, 14 cases of serious pneumonia were
reported (2 in the \< 100 mg group and 12 in the 100 mg group). None of
these were fatal. Seven were considered related to study drug by the
investigator and all subjects recovered with antibiotic treatment. Three
subjects were withdrawn from study due to pneumonia. Nine of the 14
subjects (64.3%) had a medical history of one or more chronic diseases
predisposing them to an increased risk for infection: chronic
obstructive pulmonary disease \[COPD\] (5), asthma (5), pneumonia (3),
congestive heart failure \[CHF\] (1) and coronary artery disease (1).
\[Note: some patients had more than one predisposing disease.\]

Bronchitis occurred in 3 subjects (1 each in the placebo, \< 100 mg and
100 mg anakinra groups), of which 2 were asthmatic bronchitis (1 each
receiving placebo and 100 mg anakinra). One of the 3 cases was reported
by the investigator as related to study drug (receiving 100 mg
anakinra). None of the subjects who experienced serious bronchitis were
withdrawn from study. Of note is that 2 of the 3 subjects had a medical
history of one or more chronic diseases predisposing them to an
increased risk for infection: COPD (2), pneumonia (1), CHF (1), and
diabetes mellitus (1). \[Note, some patients had more than one
predisposing disease.\]

Investigators reported events coded as "infection" in 3 subjects
receiving 100 mg anakinra daily, including 2 cases of "infection
bacterial". Two were infections of the toe or foot, and 1 was an
infected cervical spine fusion. One subject was withdrawn from the
study.

Bursitis occurred in 1 case each in the 3 anakinra groups: an olecranon
bursitis (100 mg anakinra), hospitalization for bunion surgery (75 mg
anakinra), and a bacterial elbow bursitis (150 mg anakinra).

Cellulitis occurred in 3 subjects in the 100 mg anakinra group, 2 of
which were lower extremity cellulitis; the third was reported as
unspecified "cellulitis". Gangrene of the right little toe was reported
in 1 placebo subject with confirmed atherosclerotic disease. Even though
the latter was considered "infectious" by the investigator, antibiotics
were not administered.

Two cases of osteomyelitis were reported in the 100 mg anakinra group.
One occurred in a subject with a history of a herniated disc who
developed an epidural abscess and osteomyelitis. *S aureus* and
*Pseudomonas* were isolated. The subject was not withdrawn from study
due to this event. The other, with a history of *S aureus* infection of
a toe, was hospitalized for suspected osteomyelitis. The subject was
treated with antibiotics, and was withdrawn from study after 105 days on
study.

#### Serious Infections and Corticosteroid Use

The contribution of immunosuppressive agents, such as
glucocorticosteroids, to the risk for infection was examined in the
large Safety Study (990757). This evaluation is complicated by the low
serious infection incidence (0.4%) in the placebo group in this study.
Nevertheless, the percentage of subjects using steroids at baseline was
somewhat higher among the 23 anakinra subjects with serious infections
(19 subjects \[82.6%\]) than the other anakinra subjects (617 subjects
\[56.5%\]) or placebo subjects without serious infections (171 subjects
\[60.6%\]). Steroid use among anakinra subjects with serious infections
at the time of their serious infection was higher (15 \[65.2%\])
compared with steroid use over the entire study period among anakinra
subjects without serious infections (572 \[52.3%\]). These analyses
suggest that concomitant use of corticosteroids with anakinra could
increase the risk of infection. The mean doses of steroids did not vary
greatly however: 8.0 mg/day for the 23 anakinra subjects with serious
infections, 7.0 mg/day for the anakinra subjects without serious
infections, and 7.2 mg/day for the placebo subjects without serious
infections.

#### Serious Infections in Subjects With Comorbid Conditions

The incidence of serious infections was examined in subjects with or
without a medical history of selected chronic diseases (asthma, CHF,
COPD, diabetes mellitus, coronary artery disease, and pneumonia) in the
5 randomized, placebo-controlled studies combined.

-   In subjects with a history of asthma receiving anakinra
    (Table 4-31), the incidence of serious infections is 4.5%, compared
    with 0.0% in those with a history of asthma receiving placebo.
    However, the incidence of serious infections is slightly higher in
    the subjects without asthma (anakinra 1.4%, placebo 0.7%).

-   In subjects with a history of pneumonia receiving anakinra
    (Table 4-32) the incidence of serious infections is 2.7% compared
    with 0.0% for those with a history of pneumonia receiving placebo.
    However, the incidence of serious infections is only slightly higher
    in the anakinra group compared with placebo without a history of
    pneumonia (anakinra 1.6%, placebo 0.7%).

-   The number of subjects with a history of CHF is too small (71/2932;
    2.4%) to warrant analysis.

No effect of a history of coronary artery disease, diabetes mellitus, or
COPD was seen on the risk for infection. History of asthma or pneumonia
could increase the risk of infection for subjects receiving anakinra.

Table 4‑31. Summary of Infection by History of Asthma for
Placebo-controlled Studies

<table>
<colgroup>
<col style="width: 2%" />
<col style="width: 30%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 1%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td colspan="4">Placebo</td>
<td></td>
<td colspan="4">All Anakinra</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="2">No Disease</td>
<td colspan="2">Disease</td>
<td></td>
<td colspan="2">No Disease</td>
<td colspan="2">Disease</td>
</tr>
<tr class="odd">
<td colspan="2">n (%)</td>
<td colspan="2">(N = 709)</td>
<td colspan="2">(N = 50)</td>
<td></td>
<td colspan="2">(N = 1996)</td>
<td colspan="2">(N = 177)</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>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Any</td>
<td>252</td>
<td>(35.5)</td>
<td>23</td>
<td>(46.0)</td>
<td></td>
<td>759</td>
<td>(38.0)</td>
<td>96</td>
<td>(54.2)</td>
</tr>
<tr class="even">
<td></td>
<td>Severe or Life-threatening</td>
<td>11</td>
<td>(1.6)</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>41</td>
<td>(2.1)</td>
<td>13</td>
<td>(7.3)</td>
</tr>
<tr class="odd">
<td></td>
<td>Serious</td>
<td>5</td>
<td>(0.7)</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>28</td>
<td>(1.4)</td>
<td>8</td>
<td>(4.5)</td>
</tr>
<tr class="even">
<td></td>
<td>Withdrawal</td>
<td>6</td>
<td>(0.8)</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>19</td>
<td>(1.0)</td>
<td>2</td>
<td>(1.1)</td>
</tr>
<tr class="odd">
<td colspan="11">Page 1 of 1</td>
</tr>
<tr class="even">
<td colspan="11">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="11">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="11">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="11">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="11"></td>
</tr>
<tr class="odd">
<td
colspan="11"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_hxflags_infect.sas</p>
<p>Output: t_hxflags_infect_asthma.rtf (generated 05JUL2001)</p></td>
</tr>
</tbody>
</table>

Table 4‑32. Summary of Infection by History of Pneumonia for
Placebo-controlled Studies

<table>
<colgroup>
<col style="width: 2%" />
<col style="width: 30%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 1%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td colspan="4">Placebo</td>
<td></td>
<td colspan="4">All Anakinra</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="2">No Disease</td>
<td colspan="2">Disease</td>
<td></td>
<td colspan="2">No Disease</td>
<td colspan="2">Disease</td>
</tr>
<tr class="odd">
<td colspan="2">n (%)</td>
<td colspan="2">(N = 689)</td>
<td colspan="2">(N = 70)</td>
<td></td>
<td colspan="2">(N = 1990)</td>
<td colspan="2">(N = 183)</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>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Any</td>
<td>254</td>
<td>(36.9)</td>
<td>21</td>
<td>(30.0)</td>
<td></td>
<td>760</td>
<td>(38.2)</td>
<td>95</td>
<td>(51.9)</td>
</tr>
<tr class="even">
<td></td>
<td>Severe or Life-threatening</td>
<td>11</td>
<td>(1.6)</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>46</td>
<td>(2.3)</td>
<td>8</td>
<td>(4.4)</td>
</tr>
<tr class="odd">
<td></td>
<td>Serious</td>
<td>5</td>
<td>(0.7)</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>31</td>
<td>(1.6)</td>
<td>5</td>
<td>(2.7)</td>
</tr>
<tr class="even">
<td></td>
<td>Withdrawal</td>
<td>6</td>
<td>(0.9)</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>17</td>
<td>(0.9)</td>
<td>4</td>
<td>(2.2)</td>
</tr>
<tr class="odd">
<td colspan="11">Page 1 of 1</td>
</tr>
<tr class="even">
<td colspan="11">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="11">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="11">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="11">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="11"></td>
</tr>
<tr class="odd">
<td
colspan="11"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_hxflags_infect.sas</p>
<p>Output: t_hxflags_infect_pneum.rtf (generated 05JUL2001)</p></td>
</tr>
</tbody>
</table>

####  {#section .unnumbered}

#### All RA Studies: Serious Infections

The exposure-adjusted event rates of serious infections (≥ 0.10 events
per 100 patient-year) across all RA studies were similar for the
all-studies anakinra group compared with the placebo-controlled studies
anakinra group, despite the differential follow-up periods between
groups (Table 4-33). The exposure-adjusted risk for serious infections
among anakinra subjects does not appear to increase over time.

Table 4‑33. Serious Infectious Episodes (Exposure-adjusted Event
Incidence) by Preferred Term for Placebo-controlled and All Studies\
(≥ 0.1 events/100 patient-years in Placebo-controlled Anakinra)

+---------------------------+-----+------+-----+------+---+----+------+
|                           | Pla |      |     |      |   | A  |      |
|                           | ceb |      |     |      |   | ll |      |
|                           | o-c |      |     |      |   | St |      |
|                           | ont |      |     |      |   | ud |      |
|                           | rol |      |     |      |   | ie |      |
|                           | led |      |     |      |   | s^ |      |
|                           | S   |      |     |      |   | b^ |      |
|                           | tud |      |     |      |   |    |      |
|                           | ies |      |     |      |   |    |      |
|                           | ^a^ |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
|                           | P   |      | An  |      |   | An |      |
|                           | lac |      | aki |      |   | ak |      |
|                           | ebo |      | nra |      |   | in |      |
|                           |     |      |     |      |   | ra |      |
+---------------------------+-----+------+-----+------+---+----+------+
| n (events per 100 patient | (N  |      | (N  |      |   | (N |      |
| years)                    | =   |      | =   |      |   | =  |      |
|                           | 7   |      | 21  |      |   | 2  |      |
|                           | 59) |      | 73) |      |   | 53 |      |
|                           |     |      |     |      |   | 1) |      |
|                           | 29  |      | 84  |      |   |    |      |
|                           | 6.2 |      | 5.0 |      |   | 18 |      |
|                           | pt- |      | pt- |      |   | 72 |      |
|                           | yrs |      | yrs |      |   | .9 |      |
|                           |     |      |     |      |   | pt |      |
|                           |     |      |     |      |   | -y |      |
|                           |     |      |     |      |   | rs |      |
+---------------------------+-----+------+-----+------+---+----+------+
| Any                       | 6   | (2   | 46  | (5   |   | 1  | (5   |
|                           |     | .03) |     | .44) |   | 10 | .87) |
+---------------------------+-----+------+-----+------+---+----+------+
|                           |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| Pneumonia                 | 0   | (0   | 12  | (1   |   | 18 | (0   |
|                           |     | .00) |     | .42) |   |    | .96) |
+---------------------------+-----+------+-----+------+---+----+------+
| Bursitis                  | 0   | (0   | 4   | (0   |   | 7  | (0   |
|                           |     | .00) |     | .47) |   |    | .37) |
+---------------------------+-----+------+-----+------+---+----+------+
| Cellulitis                | 0   | (0   | 3   | (0   |   | 12 | (0   |
|                           |     | .00) |     | .36) |   |    | .64) |
+---------------------------+-----+------+-----+------+---+----+------+
| Infection                 | 0   | (0   | 3   | (0   |   | 9  | (0   |
|                           |     | .00) |     | .36) |   |    | .48) |
+---------------------------+-----+------+-----+------+---+----+------+
| Abscess                   | 0   | (0   | 2   | (0   |   | 2  | (0   |
|                           |     | .00) |     | .24) |   |    | .11) |
+---------------------------+-----+------+-----+------+---+----+------+
| Bronchitis                | 1   | (0   | 2   | (0   |   | 4  | (0   |
|                           |     | .34) |     | .24) |   |    | .21) |
+---------------------------+-----+------+-----+------+---+----+------+
| Osteomyelitis             | 0   | (0   | 2   | (0   |   | 3  | (0   |
|                           |     | .00) |     | .24) |   |    | .16) |
+---------------------------+-----+------+-----+------+---+----+------+
| Pneumonia Bacterial       | 0   | (0   | 2   | (0   |   | 3  | (0   |
|                           |     | .00) |     | .24) |   |    | .16) |
+---------------------------+-----+------+-----+------+---+----+------+
| Pelvic Inflammation^c^    | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .16) |   |    | .07) |
+---------------------------+-----+------+-----+------+---+----+------+
| Appendicitis              | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| Asthma                    | 1   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .34) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| Bronchopneumonia          | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| Diarrhea                  | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| Empyema                   | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| Esophagitis               | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| Gastroenteritis           | 0   | (0   | 1   | (0   |   | 2  | (0   |
|                           |     | .00) |     | .12) |   |    | .11) |
+---------------------------+-----+------+-----+------+---+----+------+
| Herpes Zoster             | 0   | (0   | 1   | (0   |   | 2  | (0   |
|                           |     | .00) |     | .12) |   |    | .11) |
+---------------------------+-----+------+-----+------+---+----+------+
| Infection Bacterial       | 0   | (0   | 1   | (0   |   | 3  | (0   |
|                           |     | .00) |     | .12) |   |    | .16) |
+---------------------------+-----+------+-----+------+---+----+------+
| Infection Respiratory     | 1   | (0   | 1   | (0   |   | 2  | (0   |
| Tract                     |     | .34) |     | .12) |   |    | .11) |
+---------------------------+-----+------+-----+------+---+----+------+
| LRI                       | 0   | (0   | 1   | (0   |   | 2  | (0   |
|                           |     | .00) |     | .12) |   |    | .11) |
+---------------------------+-----+------+-----+------+---+----+------+
| Pleural Effusion          | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| Pyelonephritis            | 0   | (0   | 1   | (0   |   | 2  | (0   |
|                           |     | .00) |     | .12) |   |    | .11) |
+---------------------------+-----+------+-----+------+---+----+------+
| URI                       | 0   | (0   | 1   | (0   |   | 1  | (0   |
|                           |     | .00) |     | .12) |   |    | .05) |
+---------------------------+-----+------+-----+------+---+----+------+
| UTI                       | 1   | (0   | 1   | (0   |   | 4  | (0   |
|                           |     | .34) |     | .12) |   |    | .21) |
+---------------------------+-----+------+-----+------+---+----+------+
| LRI - lower respiratory   |     |      |     |      |   |    |      |
| infection                 |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| ^a^Includes studies 0560, |     |      |     |      |   |    |      |
| 960180, 960182, 990145,   |     |      |     |      |   |    |      |
| and 990757                |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| ^b^Includes studies 0505, |     |      |     |      |   |    |      |
| 0512, 0560, 0564, 0564E1, |     |      |     |      |   |    |      |
| 0564E2, 0564E3, 960180,   |     |      |     |      |   |    |      |
| 960181, 960182, 970102,   |     |      |     |      |   |    |      |
| 980220, 990145, and       |     |      |     |      |   |    |      |
| 990757                    |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| ^c^Reproductive AE rates  |     |      |     |      |   |    |      |
| are gender-specific.      |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| N = Number of randomized  |     |      |     |      |   |    |      |
| subjects who received at  |     |      |     |      |   |    |      |
| least 1 dose of study     |     |      |     |      |   |    |      |
| drug                      |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| n = Number of adverse     |     |      |     |      |   |    |      |
| events                    |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| Patient year of exposure  |     |      |     |      |   |    |      |
| is the duration between   |     |      |     |      |   |    |      |
| the first dose date and   |     |      |     |      |   |    |      |
| the last dose date.       |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+
| /s                        |     |      |     |      |   |    |      |
| tat/il1ra/fda_brfpkg/anal |     |      |     |      |   |    |      |
| ysis/safety/statfiles/tab |     |      |     |      |   |    |      |
| les/t_ae_event_rctall.sas |     |      |     |      |   |    |      |
|                           |     |      |     |      |   |    |      |
| Output:                   |     |      |     |      |   |    |      |
| t_ae_even                 |     |      |     |      |   |    |      |
| t_rctall_serinf_pterm.rtf |     |      |     |      |   |    |      |
| (generated 29JUN2001)     |     |      |     |      |   |    |      |
+---------------------------+-----+------+-----+------+---+----+------+

#### Experience From Sepsis Trials 

Because of its relevance to the use of anakinra in subjects at risk for
infection, or having an infection, infectious events from anakinra
trials in subjects with sepsis were reviewed. Data are available for
1688 subjects from 3 studies (0504, 0509, and 0556), of whom 1015
received anakinra at doses ranging from 17 mg/hour to 2 mg/kg/hour over
a 72-hour treatment period. The calculated mean dose over the 72-hour
period was up to 34.7 times the daily dose intended for use in the RA
population (100 mg). The incidence of mortality over the first 28 days
(clinical study endpoints) from these 3 studies is summarized in
Table 4-34. The incidence of any new infections (categorized using a
list of events considered infectious based on data review by Amgen
personnel, and not confirmed microbiologically), and new infections
developing after study day 3 from two of these studies are summarized in
Table 4-35. The third study (0556) was terminated early based on a
determination of lack of efficacy by the Data Monitoring Board, and
complete data on new infections from this study are not available.

Table 4‑34. Deaths by Treatment Group Within 28 Days in\
Sepsis Studies 0504, 0509 and 0556

+-----------------------+-----------------------+-----------------------+
| **Study**             | **Placebo**           | **All Anakinra^a^**   |
|                       |                       |                       |
|                       | (N = 673)             | (N = 1015)            |
|                       |                       |                       |
|                       | n/n' (%)              | n/n' (%)              |
+-----------------------+-----------------------+-----------------------+
| 0504                  | 11/25 (44.0%)         | 18/74 (24.3%)         |
+-----------------------+-----------------------+-----------------------+
| 0509                  | 102/302 (33.8%)       | 177/591 (29.9%)       |
+-----------------------+-----------------------+-----------------------+
| 0556                  | 126/346 (36.4%)       | 116/350 (33.1%)       |
+-----------------------+-----------------------+-----------------------+
| All 3 studies         | 239/673 (35.5%)       | 311/1015 (30.6%)      |
+-----------------------+-----------------------+-----------------------+
| ^a^Calculated mean    |                       |                       |
| anakinra dose from    |                       |                       |
| 1.3 to 10.4 g over 72 |                       |                       |
| hours                 |                       |                       |
|                       |                       |                       |
| N = total number of   |                       |                       |
| subjects in all 3     |                       |                       |
| studies               |                       |                       |
|                       |                       |                       |
| n = number of deaths  |                       |                       |
| in each study         |                       |                       |
|                       |                       |                       |
| n' = number of        |                       |                       |
| subjects in study     |                       |                       |
|                       |                       |                       |
| \% = n/n' x 100       |                       |                       |
+-----------------------+-----------------------+-----------------------+

Table 4‑35. Treatment-Emergent Infections By Treatment Group in\
Sepsis Studies 0504 and 0509 Combined^a^

+--------------------------+--------------------+---------------------+
|                          | **Placebo**        | **All Anakinra**    |
|                          |                    |                     |
|                          | n/N (%)            | n/N (%)             |
+--------------------------+--------------------+---------------------+
| All Infections           | 65/327 (19.9%)     | 132/665 (19.8%)     |
+--------------------------+--------------------+---------------------+
| All Infections After     | 48/290 (16.6%)     | 111/633 (17.5%)     |
| Study Day 3              |                    |                     |
+--------------------------+--------------------+---------------------+
| All Infections After     | 5/290 (1.7%)       | 13/633 (2.1%)       |
| Study Day 3 Resulting In |                    |                     |
| Death                    |                    |                     |
+--------------------------+--------------------+---------------------+
| ^a^Data from study 0556  |                    |                     |
| were not available to    |                    |                     |
| summarize in this        |                    |                     |
| format.                  |                    |                     |
|                          |                    |                     |
| N = total number of      |                    |                     |
| subjects in each study   |                    |                     |
|                          |                    |                     |
| n = number of infections |                    |                     |
| in each study            |                    |                     |
|                          |                    |                     |
| \% = n/N x 100           |                    |                     |
+--------------------------+--------------------+---------------------+

The incidence of mortality in the all anakinra group is consistently
lower in all 3 sepsis studies compared with the placebo group, with an
overall incidence of mortality of 30.6% in the anakinra group and 35.5%
in the placebo group. The incidence of new infections in 2 of the 3
studies is similar in the two groups. These data from the sepsis trials
further support the safety observations of anakinra use in subjects with
RA.

#### Summary of Infections 

Overall, in the randomized, placebo-controlled studies, the subject
incidence of any infection is similar in the anakinra treatment group
compared to the placebo group (39.3% anakinra, 36.2% placebo). Severe or
life-threatening infections occurred in 2.5% of all anakinra subjects,
compared with 1.4% of subjects in the placebo group. Serious infections
occurred in 1.7% of all anakinra subjects compared with 0.7% in the
placebo group, and the incidence of withdrawals due to infections is low
in both anakinra and placebo groups (1% anakinra, 0.8% placebo).

The exposure-adjusted event rates of serious infections across all RA
studies were similar for the all-studies anakinra group compared with
the placebo-controlled studies anakinra group (5.44 vs 5.87 events/100
patient-years, respectively), despite the differential follow-up periods
between groups. This finding suggests that the risk for serious
infections among anakinra subjects does not increase over time.

Post-hoc analyses of potential risk factors for infection indicated that
the risk of having a serious infection may be slightly higher in
anakinra treated subjects either receiving corticosteroid treatment, or
with a history of asthma or pneumonia.

### Malignancies

All reported malignancies for subjects participating in any anakinra RA
trials are listed in Table 4-36. A total of 30 subjects had malignancies
(6 placebo \[crude incidence = 0.8%\], 23 anakinra \[crude incidence =
0.9%\], and 1 case in the Confirmatory Efficacy Study \[990145\], which
remains blinded). The observed difference in numbers of subjects with
malignancies between the anakinra and placebo groups is consistent with
the greater number of subjects treated with anakinra versus placebo, as
well as the longer mean patient exposure to anakinra (38.6 weeks)
compared with placebo (20.3 weeks; Table 4-18).

The exposure-adjusted malignancy rate per 100 patient-years of study
drug exposure is 1.2 for anakinra treated subjects and 2.0 for placebo
subjects.

The most common event identified as a malignancy was breast cancer (6
cases in the anakinra group). Histology is available from 4 of these
subjects and all were identified as ductal carcinomas. Five basal cell
carcinomas were reported (1 placebo, 4 anakinra); 1 squamous cell skin
carcinoma and 1 metastatic melanoma were reported in the placebo and
anakinra groups, respectively. Lung cancer occurred in 4 subjects (2
placebo, 2 anakinra). Prostate cancer occurred in 2 subjects (1
anakinra, 1 blinded in the Confirmatory Efficacy Study \[990145\]).
Thyroid cancer was reported in 2 anakinra subjects and 1 case each of
bladder, pancreatic, cecal, oral, uterine, non-Hodgkin's lymphoma, and
gastric cancer occurred in the anakinra group. Finally, one case each of
bladder cancer and Hodgkin's lymphoma were reported in the placebo
group.

Table 4‑36. Listing of Malignancies Reported in All RA Studies

+-----+------+-------+---+-------+-------+-------------+-------------+
| St  | Dose | Days  | A | Years | Rel   | Clinical    | Histology   |
| udy |      | exp   | g | since | evant | p           | report      |
|     |      | osure | e | meno  | c     | resentation |             |
|     |      | to    |   | pause | oncom |             |             |
|     |      | ana   |   |       | itant |             |             |
|     |      | kinra |   |       | m     |             |             |
|     |      | prior |   |       | edica |             |             |
|     |      | to    |   |       | tions |             |             |
|     |      | diag  |   |       |       |             |             |
|     |      | nosis |   |       |       |             |             |
+-----+------+-------+---+-------+-------+-------------+-------------+
| ##  |      |       |   |       |       |             |             |
| ### |      |       |   |       |       |             |             |
| ##  |      |       |   |       |       |             |             |
| Fem |      |       |   |       |       |             |             |
| ale |      |       |   |       |       |             |             |
|  Ca |      |       |   |       |       |             |             |
|  br |      |       |   |       |       |             |             |
| eas |      |       |   |       |       |             |             |
| t { |      |       |   |       |       |             |             |
| #fe |      |       |   |       |       |             |             |
| mal |      |       |   |       |       |             |             |
| e-c |      |       |   |       |       |             |             |
| a-b |      |       |   |       |       |             |             |
| rea |      |       |   |       |       |             |             |
| st  |      |       |   |       |       |             |             |
| .un |      |       |   |       |       |             |             |
| num |      |       |   |       |       |             |             |
| ber |      |       |   |       |       |             |             |
| ed} |      |       |   |       |       |             |             |
+-----+------+-------+---+-------+-------+-------------+-------------+
| 056 | 150  | 775   | 7 | 30    |       | 2 cm breast | Not         |
| 4E1 | mg/d |       | 3 |       |       | mass        | available   |
|     |      |       |   | (surg |       | Mammography |             |
|     |      |       |   | ical) |       | and         |             |
|     |      |       |   |       |       | ultrasound  |             |
|     |      |       |   |       |       | "suggestive |             |
|     |      |       |   |       |       | of          |             |
|     |      |       |   |       |       | carcinoma"  |             |
|     |      |       |   |       |       |             |             |
|     |      |       |   |       |       | I           |             |
|     |      |       |   |       |       | nvestigator |             |
|     |      |       |   |       |       | states      |             |
|     |      |       |   |       |       | patient has |             |
|     |      |       |   |       |       | Ca breast   |             |
+-----+------+-------+---+-------+-------+-------------+-------------+
| 960 | 2.0  | 60    | 6 | 19    |       | Breast mass | Not         |
| 180 | mg/  |       | 9 |       |       |             | available   |
|     | kg/d |       |   |       |       | Diagnosis   |             |
|     |      |       |   |       |       | carcinoma   |             |
+-----+------+-------+---+-------+-------+-------------+-------------+
| 960 | 0.4  | 343   | 7 | 22    | Pr    | Breast mass | N           |
| 181 | mg/  |       | 2 |       | overa |             | on-invasive |
|     | kg/d |       |   |       | 4 y   |             | ductal      |
|     |      |       |   |       |       |             | carcinoma   |
|     |      |       |   |       | Est   |             |             |
|     |      |       |   |       | rogen |             |             |
|     |      |       |   |       | 4 y   |             |             |
+-----+------+-------+---+-------+-------+-------------+-------------+
| 960 | 0.4  | 165   | 6 | 18    | Pr    | Lesion on   | Ductal      |
| 181 | mg/  |       | 7 |       | overa | screening   | carcinoma   |
|     | kg/d |       |   |       | 8 y   | mammogram   | in situ.    |
|     |      |       |   |       |       |             |             |
|     |      |       |   |       | Pre   |             |             |
|     |      |       |   |       | marin |             |             |
|     |      |       |   |       | 8 y   |             |             |
+-----+------+-------+---+-------+-------+-------------+-------------+
| 960 | 0.4  | 296   | 5 | 16    | Pre   | Mammogram   | 0.4 cm      |
| 181 | mg/  |       | 4 |       | marin |             | i           |
|     | kg/d |       |   |       | 2 y   |             | nfiltrating |
|     |      |       |   |       |       |             | ductal      |
|     |      |       |   |       |       |             | carcinoma   |
+-----+------+-------+---+-------+-------+-------------+-------------+
| 960 | 0.4  | 274   | 6 | 16    |       | Nipple      | I           |
| 181 | mg/  |       | 7 |       |       | retraction  | nfiltrating |
|     | kg/d |       |   |       |       |             | ductal      |
|     |      |       |   |       |       |             | carcinoma   |
|     |      |       |   |       |       |             | grade 3     |
+-----+------+-------+---+-------+-------+-------------+-------------+
|     |      |       |   |       |       |             | Page 1 of 4 |
+-----+------+-------+---+-------+-------+-------------+-------------+
| /s  |      |       |   |       |       |             |             |
| tat |      |       |   |       |       |             |             |
| /il |      |       |   |       |       |             |             |
| 1ra |      |       |   |       |       |             |             |
| /fd |      |       |   |       |       |             |             |
| a_b |      |       |   |       |       |             |             |
| rfp |      |       |   |       |       |             |             |
| kg/ |      |       |   |       |       |             |             |
| ana |      |       |   |       |       |             |             |
| lys |      |       |   |       |       |             |             |
| is/ |      |       |   |       |       |             |             |
| saf |      |       |   |       |       |             |             |
| ety |      |       |   |       |       |             |             |
| /st |      |       |   |       |       |             |             |
| atf |      |       |   |       |       |             |             |
| ile |      |       |   |       |       |             |             |
| s/l |      |       |   |       |       |             |             |
| ist |      |       |   |       |       |             |             |
| ing |      |       |   |       |       |             |             |
| s/l |      |       |   |       |       |             |             |
| _ma |      |       |   |       |       |             |             |
| lig |      |       |   |       |       |             |             |
| nan |      |       |   |       |       |             |             |
| cy. |      |       |   |       |       |             |             |
| doc |      |       |   |       |       |             |             |
| (1  |      |       |   |       |       |             |             |
| 2JU |      |       |   |       |       |             |             |
| L20 |      |       |   |       |       |             |             |
| 01) |      |       |   |       |       |             |             |
+-----+------+-------+---+-------+-------+-------------+-------------+

Table 4-32. Listing of Malignancies Reported in All RA Studies
(Continued)

  --------------- ------ ----------- ----- --------- -------------- ------ -------------- ------ ------------------
  Study           Dose   Days        Age   Sex       Relevant              Clinical              Histology report
                         exposure to                 History               presentation          
                         anakinra                                                                
                         prior to                                                                
                         diagnosis                                                               

  **Other                                                                                        
  Malignacies**                                                                                  

  0505/ 0512      20     126         n/a   M                               "Carcinoma of         Not available
                  mg/d                                                     prostate"             

  0560            30     58          73    M                               Oral mass             Medium/highly
                  mg/d                                                                           differentiated
                                                                                                 squamous carcinoma
                                                                                                 of mouth

  0560            30     183         55    M         Smoker                Hoarseness and        Biopsy mediastinal
                  mg/d                                                     chest X-ray           nodes and marrow
                                                                           picture               -- small cell lung
                                                                                                 carcinoma

  0560            150    125         74    F         Two basal cell        Lesion R cheek        Basal cell
                  mg/d                               carcinomas                                  carcinoma
                                                     pre-anakinra                                

  0560            150    43          53    F         Multinodular                                Papillomatous
                  mg/d                               goiter                                      carcinoma of
                                                                                                 thyroid

  0560            30     157         75    M         Smoker                "Lung cancer"         Not available
                  mg/d                                                     by CAT scan           

  0564            30     20          58    F                               Sweating and          Undifferentiated
                  mg/d                                                     nodule                carcinoma of
                                                                                                 thyroid

  0564            75     498         67    M                               Dyspepsia and         Adenocarcinoma in
                  mg/d                                                     dysphagia             gastroscopic
                                                                                                 biopsy

                                                                                                 Page 2 of 4
  --------------- ------ ----------- ----- --------- -------------- ------ -------------- ------ ------------------

Table 4-32. Listing of Malignancies Reported in All RA Studies
(Continued)

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 4%" />
<col style="width: 1%" />
<col style="width: 4%" />
<col style="width: 14%" />
<col style="width: 21%" />
<col style="width: 1%" />
<col style="width: 22%" />
<col style="width: 0%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Study</td>
<td colspan="3">Dose</td>
<td colspan="2">Days exposure to anakinra prior to diagnosis</td>
<td colspan="2">Age</td>
<td>Sex</td>
<td>Relevant History</td>
<td colspan="2">Clinical presentation</td>
<td colspan="2">Histology report</td>
</tr>
<tr class="even">
<td><strong>Others</strong></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>0564E2</td>
<td colspan="3">75 mg/d</td>
<td colspan="2">1235</td>
<td colspan="2">79</td>
<td>M</td>
<td></td>
<td colspan="2"></td>
<td colspan="2">Adenocarcinoma of pancreas</td>
</tr>
<tr class="even">
<td>960180</td>
<td colspan="3">Placebo</td>
<td colspan="2">0</td>
<td colspan="2">64</td>
<td>M</td>
<td>Smoker</td>
<td colspan="2">5 cm pulmonary mass on CT scan</td>
<td colspan="2">Needle biopsy – large cell carcinoma</td>
</tr>
<tr class="odd">
<td>960181</td>
<td colspan="3">0.4 mg/kg/d</td>
<td colspan="2">358</td>
<td colspan="2">69</td>
<td>M</td>
<td></td>
<td colspan="2">Lesion on nose</td>
<td colspan="2">Basal cell carcinoma</td>
</tr>
<tr class="even">
<td>960181</td>
<td colspan="3">0.4 mg/kg/d</td>
<td colspan="2">295</td>
<td colspan="2">72</td>
<td>M</td>
<td>Prior history basal cell carcinoma</td>
<td colspan="2">“Basal cell carcinoma” upper right back</td>
<td colspan="2">Not Available</td>
</tr>
<tr class="odd">
<td>970102</td>
<td colspan="3">30 mg/d</td>
<td colspan="2">303</td>
<td colspan="2">81</td>
<td>F</td>
<td><p>Bladder Ca</p>
<p>Several previous resections</p></td>
<td colspan="2"><p>“Routine” cystoscopy</p>
<p>Bladder adenoma</p></td>
<td colspan="2">Not available</td>
</tr>
<tr class="even">
<td>980220</td>
<td colspan="3">150 mg/d</td>
<td colspan="2">126</td>
<td colspan="2">51</td>
<td>F</td>
<td>Suspicious biopsy L post-auricular lymph node 1/98, 11 months before
exposure to anakinra</td>
<td colspan="2">Post-auricular, sub-occipital and jugular
lymphadenopathy</td>
<td colspan="2">Non-Hodgkin’s lymphoma</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="4"></td>
<td colspan="2">Page 3 of 4</td>
<td></td>
</tr>
</tbody>
</table>

Table 4-32. Listing of Malignancies Reported in All RA Studies
(Continued)

  ------------ --------- ----------- ----- ----- ------------ ---------------- -----------------
  Study        Dose      Days        Age   Sex   Relevant     Clinical         Histology report
                         exposure to             History      presentation     
                         anakinra                                              
                         prior to                                              
                         diagnosis                                             

  **Others**                                                                   

  990757       Placebo   31          80    F     Basal cell   Basal cell       Not available
                                                 carcinoma of carcinoma (nose) 
                                                 nose removed                  

  990757       Placebo   112         68    M     Actinic      Squamous cell    Not available
                                                 ketatosis    carcinoma of the 
                                                              skin             

  990757       Placebo   142         36    F                  Hodgkin's        Hodgkin's
                                                              lymphoma         lymphoma

  990757       Placebo   137         68    F     Cystitis,    Bladder          Papillary
                                                 renal        carcinoma        urothelial
                                                 infection                     carcinoma, low
                                                                               grade

  990757       Placebo   156         69    F     COPD,        Squamous cell    Squamous cell
                                                 shingles     carcinoma of the carcinoma
                                                              lung             

  990757       100 mg/d  105         67    M     melanoma     Metastatic       Not available
                                                              malignant        
                                                              melanoma         

  990757       100 mg/d  113         79    F                  Adenocarcinoma   Adenocarcinoma,
                                                              of cecum         moderately to
                                                                               poorly
                                                                               differentiated

  990757       100 mg/d  138         62    F     Vaginal      Uterine          Not available
                                                 bleeding     carcinoma        

  990757       100 mg/d  143         63    M                  Basal cell       Not available
                                                              carcinoma        

  990145       Blinded   43          83    M     Prostatism   Prostate cancer  Not available
  ------------ --------- ----------- ----- ----- ------------ ---------------- -----------------

> n = not available Page 4 of 4
>
> {Sources: Clinical Experience Summary (MAA amended) 5 May 2000;
> Listing provided by A. Wang on 15 June 2001.}

#### Malignancies: Comparison to SEER Statistics

The observed rates of malignancies in the anakinra group were compared
with age- and sex-adjusted expected rates based on the National Cancer
Institute's Surveillance, Epidemiology, and End Results (SEER) program
^71^. Age- and sex-specific patient-years at risk were calculated from
the date of first exposure to anakinra through the end of follow-up,
withdrawal, or 31 August 1999 for data submitted in the original BLA,
whichever occurred first. Six-month data from the Confirmatory Efficacy
Study (990145) and the large Safety Study (990757) were also included.
Eight malignancies in the anakinra group were excluded from the
comparison with the SEER statistics. The 2 breast ductal carcinomas in
situ and the 4 basal cell carcinomas were omitted because the SEER
statistics exclude basal cell carcinoma and non-invasive (in situ)
events. One case of bladder cancer and another of metastatic malignant
melanoma were excluded because they are relapses rather than new events,
and relapsed events and reoccurrences are not included in the SEER event
rates. It should also be noted that the reported prostate cancer in
study 990145 remains blinded; nevertheless, this event was included in
this comparison to the SEER database under the conservative assumption
that the subject was randomized to receive anakinra.

From (Table 4-37), the expected numbers of malignancies derived from the
SEER database are similar to the rates observed for all anakinra treated
subjects. In addition, these expected numbers are within the 95%
confidence intervals calculated from the observed data. In summary,
there does not appear to be any association between the risk of
malignancy and long term anakinra treatment.

Table 4‑37. Observed and Expected Events for Selected Invasive
Malignancies

+---------------------+---------------+---------------+---------------+
|                     | All Anakinra  |               |               |
|                     | Subjects      |               |               |
+---------------------+---------------+---------------+---------------+
|                     | Observed      | 95%           | Expected ^a^  |
|                     |               | Confidence    |               |
|                     |               | Interval      |               |
+---------------------+---------------+---------------+---------------+
| Total malignancies  | 16            | 9.70, 26.22   | 15.6          |
+---------------------+---------------+---------------+---------------+
| > Leukemias         | 0             | 0.00, 4.76    | 0.84          |
+---------------------+---------------+---------------+---------------+
| > Non-Hodgkin's     | 1             | 0.00, 6.38    | 0.58          |
| > lymphoma          |               |               |               |
+---------------------+---------------+---------------+---------------+
| Women               |               |               |               |
+---------------------+---------------+---------------+---------------+
| > All malignancies  | 9             | 4.51, 17.43   | 10.24         |
+---------------------+---------------+---------------+---------------+
| > Breast cancer     | 4             | 1.21, 10.76   | 3.53          |
+---------------------+---------------+---------------+---------------+
| Men                 |               |               |               |
+---------------------+---------------+---------------+---------------+
| > All malignancies  | 7             | 3.15, 14.70   | 5.38          |
+---------------------+---------------+---------------+---------------+
| > Prostate cancer   | 2             | 0.10, 7.84    | 1.82          |
+---------------------+---------------+---------------+---------------+
| ^a^ Based on        |               |               |               |
| National Cancer     |               |               |               |
| Institute's         |               |               |               |
| Surveillance        |               |               |               |
| Epidemiology and    |               |               |               |
| End Results (SEER)  |               |               |               |
| statistics.         |               |               |               |
+---------------------+---------------+---------------+---------------+

### Adverse Events By Gender

The adverse event profiles for men and women from the 5 randomized
placebo-controlled studies are shown in Table 4-38. The profiles are
similar for female and male subjects having any adverse events, SAEs,
severe adverse events, or infections. The subject incidence of ISRs was
higher in females subjects receiving anakinra (70.2%) compared with male
subjects (46.0%).

### Adverse Events By Age

The adverse event profiles for subjects \< 65 and ≥ 65 years old from
the 5 randomized placebo-controlled studies are shown in Table 4-39. The
profiles are similar for subjects having any AEs, SAEs, or infections.
Older subjects in both groups had a higher incidence of SAEs compared
with younger subjects, which is not unexpected due to a higher
likelihood of hospitalization for disease in the elderly. Interestingly,
ISRs in the anakinra group occurred at a lower incidence in the older
group compared with younger subjects.

Table 4‑38. Summary of Overall AEs by Gender (Placebo/Anakinra) in\
Placebo-Controlled Studies

+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   | Placebo   |           | Anakinra  |           |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   | Female    | Male      | Female    | Male      |
+-----------------+---+-----------+-----------+-----------+-----------+
| n (%)           |   | (N = 567) | (N = 192) | (N =      | (N = 522) |
|                 |   |           |           | 1651)     |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Any Adverse     |   | 486       | 159       | 1536      | 446       |
| Event           |   | (85.7)    | (82.8)    | (93.0)    | (85.4)    |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Serious Adverse |   | 36 (6.3)  | 13 (6.8)  | 128 (7.8) | 44 (8.4)  |
| Event           |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Severe Adverse  |   | 84 (14.8) | 36 (18.8) | 268       | 68 (13.0) |
| Event           |   |           |           | (16.2)    |           |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Infectious      |   | 213       | 62 (32.3) | 681       | 174       |
| Episodes        |   | (37.6)    |           | (41.2)    | (33.3)    |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Injection Site  |   | 166       | 38 (19.8) | 1159      | 240       |
| Reaction        |   | (29.3)    |           | (70.2)    | (46.0)    |
+-----------------+---+-----------+-----------+-----------+-----------+
| Includes        |   |           |           |           |           |
| studies 0560,   |   |           |           |           |           |
| 960180, 960182, |   |           |           |           |           |
| 990145, and     |   |           |           |           |           |
| 990757          |   |           |           |           |           |
|                 |   |           |           |           |           |
| N = Number of   |   |           |           |           |           |
| randomized      |   |           |           |           |           |
| subjects who    |   |           |           |           |           |
| received at     |   |           |           |           |           |
| least 1 dose of |   |           |           |           |           |
| study drug      |   |           |           |           |           |
|                 |   |           |           |           |           |
| n = Number of   |   |           |           |           |           |
| subjects        |   |           |           |           |           |
| reporting at    |   |           |           |           |           |
| least 1         |   |           |           |           |           |
| occurrence of   |   |           |           |           |           |
| an adverse      |   |           |           |           |           |
| event           |   |           |           |           |           |
|                 |   |           |           |           |           |
| \% = (n/N) x    |   |           |           |           |           |
| 100             |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+

Table 4‑39. Summary of Overall AEs by Age (Placebo/Anakinra) in
Placebo-Controlled Studies

+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   | Placebo   |           | Anakinra  |           |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   | Age \< 65 | Age \>=   | Age \< 65 | Age \>=   |
|                 |   |           | 65        |           | 65        |
+-----------------+---+-----------+-----------+-----------+-----------+
| n (%)           |   | (N = 570) | (N = 189) | (N =      | (N = 464) |
|                 |   |           |           | 1709)     |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Any Adverse     |   | 483       | 162       | 1554      | 428       |
| Event           |   | (84.7)    | (85.7)    | (90.9)    | (92.2)    |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Serious Adverse |   | 33 (5.8)  | 16 (8.5)  | 115 (6.7) | 57 (12.3) |
| Event           |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Severe Adverse  |   | 87 (15.3) | 33 (17.5) | 256       | 80 (17.2) |
| Event           |   |           |           | (15.0)    |           |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Infectious      |   | 214       | 61 (32.3) | 690       | 165       |
| Episodes        |   | (37.5)    |           | (40.4)    | (35.6)    |
+-----------------+---+-----------+-----------+-----------+-----------+
|                 |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+
| Injection Site  |   | 160       | 44 (23.3) | 1140      | 259       |
| Reaction        |   | (28.1)    |           | (66.7)    | (55.8)    |
+-----------------+---+-----------+-----------+-----------+-----------+
| Includes        |   |           |           |           |           |
| studies 0560,   |   |           |           |           |           |
| 960180, 960182, |   |           |           |           |           |
| 990145, and     |   |           |           |           |           |
| 990757          |   |           |           |           |           |
|                 |   |           |           |           |           |
| N = Number of   |   |           |           |           |           |
| randomized      |   |           |           |           |           |
| subjects who    |   |           |           |           |           |
| received at     |   |           |           |           |           |
| least 1 dose of |   |           |           |           |           |
| study drug      |   |           |           |           |           |
|                 |   |           |           |           |           |
| n = Number of   |   |           |           |           |           |
| subjects        |   |           |           |           |           |
| reporting at    |   |           |           |           |           |
| least 1         |   |           |           |           |           |
| occurrence of   |   |           |           |           |           |
| an adverse      |   |           |           |           |           |
| event           |   |           |           |           |           |
|                 |   |           |           |           |           |
| \% = (n/N) x    |   |           |           |           |           |
| 100             |   |           |           |           |           |
+-----------------+---+-----------+-----------+-----------+-----------+

### Laboratory Parameters

The inflammatory process in RA is associated with changes in several
parameters, including platelet count (thrombocytosis), hemoglobin level
(anemia), and WBC count (leukocytosis, leukopenia, eosinophilia). Based
on the biological effects of anakinra (ie, blocking IL-1 effects), it is
not unexpected to find that treatment with anakinra resulted in changes
in these parameters towards more normal values.

Changes in mean values in laboratory parameters in the Confirmatory
Efficacy Study (990145) and the Safety Study (990757) over time, are
summarized. Abnormalities (Grade 2 to Grade 4 shifts) in hepatic, renal
and hematologic parameters in all 5 randomized, placebo-controlled
studies are also reviewed.

##### Mean Changes in Laboratory Parameters

Anakinra treatment results in a reduction in mean values for WBCs,
platelets and neutrophils from slightly high baseline values to values
which are closer to the midpoint of the reference range (Figure 4-25).
Mean WBC and neutrophil counts in subjects receiving 100 mg anakinra or
placebo in the large Safety Study (990757) and the Confirmatory Efficacy
Study (990145), show a slight decrease in mean WBC counts, mainly caused
by a decrease in neutrophil counts (Figure 4-25). This decrease occurs
within the first 4 weeks on study, and mean values stay well within the
reference range, and no further decreases are seen with continued
treatment. Mean lymphocyte counts remain stable in both treatment
groups.

A slight decrease in mean platelet counts relative to baseline in the
anakinra group is also seen. Similar to the pattern observed for WBC and
neutrophil counts, this decrease also occurs within the first 4 weeks on
study, the mean value stays well within the reference range, and no
further decrease is seen with continued treatment.

An increase in the mean hemoglobin level towards normal is seen in the
100 mg anakinra group compared with placebo.

Figure 4‑25. Summary of Hematologic Parameters for Studies 990145 and
990757

![](media/image36.wmf){width="7.723611111111111in"
height="5.402777777777778in"}

##### Grade 2 to Grade 4 Shifts in Laboratory Parameters

Treatment-emergent (worsening, or increase from baseline grade) Grade 2
to Grade 4 shifts in renal, hepatic, and hematologic laboratory
parameters, based on Amgen-modified World Health Organization (WHO)
toxicity criteria (Appendix 4-14), for all 5 randomized
placebo-controlled studies are summarized in Table 4-40 and discussed in
the following sections.

####### Hepatic and Renal Parameters {#hepatic-and-renal-parameters .FlushLeftBold .unnumbered}

The distribution of Grade 2 and 3 shifts for hepatic and renal
parameters is similar in the anakinra and placebo groups. No Grade 4
shifts were recorded for any of these parameters. No Grade 3 shifts were
recorded for renal parameters.

Six Grade 3 hepatic shifts were observed, 2 (0.3%) with placebo and 4
(0.2%) with anakinra. All anakinra subjects who experienced these
abnormalities were also receiving concomitant drugs, which are
associated with liver enzyme abnormalities. There were no Grade 3 shifts
in serum bilirubin levels.

-   Placebo (2 subjects): alkaline phosphatase elevation from 415 IU/L
    to 609 IU/L and ALT elevation from 55 IU/L to 194 IU/L.

-   100 mg anakinra (3 subjects): ALT elevation from 24 IU/L to 185 IU/L
    (concomitant drug MTX), from 23 IU/L to 206 IU/L (concomitant drugs
    MTX, fexofenadine, atorvastatin, pravastatin), from 53 IU/L to 238
    IU/L (concomitant drug leflunomide).

-   \> 100 mg anakinra (1 subject): ALT elevation from 20 IU/L to 238
    IU/L (concomitant medication diclofenac).

####### Hemoglobin and Platelets {#hemoglobin-and-platelets .FlushLeftBold .unnumbered}

No Grade 4 hemoglobin decreases were seen. The distribution of Grade 2
and 3 decreases was similar across groups. No platelet decreases of
Grade 2 or higher were recorded. Ten subjects (5 \[0.7%\] placebo, 5
\[0.2%\] anakinra) had Grade 3 decreases in hemoglobin. Events in the 5
anakinra subjects are described below:

-   1 subject (anakinra) had melena and a peptic ulcer at the time of
    the anemia (baseline hemoglobin 11.2 g/dL; 6.1 g/dL at the time of
    the event). Subject was also being treated concomitantly with
    NSAIDS.

-   1 subject (anakinra), with a history of multinodular goiter, was
    diagnosed with a thyroid neoplasm (baseline hemoglobin 11.8 g/dL;
    8.7 g/dL at the time of diagnosis and 7.2 g/dL at the nadir).

-   3 subjects (anakinra) had baseline abnormalities (2 with Grade 1,
    and 1 with Grade 2). One of these 3 only had a spurious decrease
    (one value of 6.8 g/dL compared with values of 11.8 and 11.6 g/dL at
    adjacent time points). Another of these 3 subjects, who had a
    baseline hemoglobin of 10.0 g/dL, had ISR ecchymosis, URI and UTI,
    which likely contributed to the anemia.

####### WBCs {#wbcs .FlushLeftBold .unnumbered}

There was a somewhat higher number of Grade 2 decreases among anakinra
subjects \[34 (1.6%)\] compared with placebo \[2 (0.3%)\].

One subject, in the MTX Combination Study (960180) receiving 0.4 mg/kg
anakinra, with a normal baseline WBC count (4.8 x 10^9^/L), had a Grade
3 WBC decrease on day 88 which was the result of a Grade 3 neutropenia.

Table 4‑40. Laboratory Parameters: Treatment-emergent Grade 2 to Grade 4
Toxicities (Worst Post Baseline Value)\
in Placebo-controlled Studies

  --------------- ------------ --------------- --------- ------- -- ---------- ------- -- ------- ------- -- ------ ------- -- ------- ------- --
                                                                    Anakinra                                                                   
                                                                    (mg)                                                                       

                                               Placebo              \< 100                100                \> 100            All             

  n (%)                                        (N = 759)            (N = 610)             (N =               (N =              (N =            
                                                                                          1367)              196)              2173)           

  Hepatic^a^                                   m = 741              m = 607               m =                m =               m =             
                                                                                          1314               192               2113            

                  Grade 2                      12        (1.6)      6          (1.0)      22      (1.7)      1      (0.5)      29      (1.4)   

                  Grade 3                      2         (0.3)      0          (0.0)      3       (0.2)      1      (0.5)      4       (0.2)   

                  Grade 4                      0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                                                                                                                                               

  Renal^b^                                     m = 741              m = 607               m =                m =               m =             
                                                                                          1314               192               2113            

                  Grade 2                      0         (0.0)      0          (0.0)      1       (0.1)      1      (0.5)      2       (0.1)   

                  Grade 3                      0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                  Grade 4                      0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                                                                                                                                               

  Hematologic                                                                                                                                  

                  Hemoglobin                   m = 739              m = 609               m =                m =               m =             
                  decrease                                                                1307               191               2107            

                               Grade 2         12        (1.6)      12         (2.0)      7       (0.5)      4      (2.1)      23      (1.1)   

                               Grade 3         5         (0.7)      2          (0.3)      1       (0.1)      2      (1.1)      5       (0.2)   

                               Grade 4         0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                                                                                                                                               

                  Platelet                     m = 736              m = 607               m =                m =               m =             
                  decrease                                                                1300               190               2097            

                               Grade 2         0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                               Grade 3         0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                               Grade 4         0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

  Page 1 of 2                                                                                                                                  

  Includes                                                                                                                                     
  studies 0560,                                                                                                                                
  960180, 960182,                                                                                                                              
  990145, and                                                                                                                                  
  990757                                                                                                                                       

  N = Number of                                                                                                                                
  subjects who                                                                                                                                 
  were randomized                                                                                                                              
  and received at                                                                                                                              
  least 1 dose of                                                                                                                              
  study drug                                                                                                                                   

  m = Number of                                                                                                                                
  evaluable                                                                                                                                    
  subjects with                                                                                                                                
  non-missing                                                                                                                                  
  baseline and                                                                                                                                 
  post-baseline                                                                                                                                
  WHOTOX grades                                                                                                                                

  \% = (n/m) x                                                                                                                                 
  100                                                                                                                                          

  ^a^ Includes                                                                                                                                 
  AST, ALT,                                                                                                                                    
  Alkaline                                                                                                                                     
  Phosphatase,                                                                                                                                 
  and Total                                                                                                                                    
  Bilirubin                                                                                                                                    

  ^b^ Includes                                                                                                                                 
  BUN and                                                                                                                                      
  Creatinine                                                                                                                                   
  --------------- ------------ --------------- --------- ------- -- ---------- ------- -- ------- ------- -- ------ ------- -- ------- ------- --

**Table 4-36.** **Laboratory Parameters: Treatment-emergent Grade 2 to
Grade 4 Toxicities (Worst Post Baseline Value)\
in Placebo-controlled Studies (Continued)**

  --------------- ------------ --------------- --------- ------- -- ---------- ------- -- ------- ------- -- ------ ------- -- ------- ------- --
                                                                    Anakinra                                                                   
                                                                    (mg)                                                                       

                                               Placebo              \< 100                100                \> 100            All             

  n (%)                                        (N = 759)            (N = 610)             (N =               (N =              (N =            
                                                                                          1367)              196)              2173)           

                                                                                                                                               

  Hematologic                                                                                                                                  
  (Cont\'d)                                                                                                                                    

                  WBC decrease                 m = 739              m = 609               m =                m =               m =             
                                                                                          1308               191               2108            

                               Grade 2         2         (0.3)      12         (2.0)      17      (1.3)      5      (2.6)      34      (1.6)   

                               Grade 3         0         (0.0)      1          (0.2)      0       (0.0)      0      (0.0)      1       (0.1)   

                               Grade 4         0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                                                                                                                                               

                  Neutrophil                   m = 736              m = 609               m =                m =               m =             
                  decrease                                                                1303               191               2103            

                               Grade 2         2         (0.3)      5          (0.8)      26      (2.0)      3      (1.6)      34      (1.6)   

                               Grade 3         0         (0.0)      4          (0.7)      1       (0.1)      1      (0.5)      6       (0.3)   

                               Grade 4         0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

                                                                                                                                               

                  Lymphocyte                   m = 736              m = 609               m =                m =               m =             
                  decrease                                                                1304               191               2104            

                               Grade 2         49        (6.7)      36         (5.9)      38      (2.9)      17     (8.9)      91      (4.3)   

                               Grade 3         17        (2.3)      14         (2.3)      13      (1.0)      6      (3.1)      33      (1.6)   

                               Grade 4         0         (0.0)      3          (0.5)      1       (0.1)      2      (1.1)      6       (0.3)   

                                                                                                                                               

                  Eosinophil                   m = 736              m = 609               m =                m =               m =             
                  increase                                                                1304               191               2104            

                               Grade 2         1         (0.1)      3          (0.5)      6       (0.5)      1      (0.5)      10      (0.5)   

                               Grade 3         0         (0.0)      0          (0.0)      2       (0.2)      0      (0.0)      2       (0.1)   

                               Grade 4         0         (0.0)      0          (0.0)      0       (0.0)      0      (0.0)      0       (0.0)   

  Page 2 of 2                                                                                                                                  

  Includes                                                                                                                                     
  studies 0560,                                                                                                                                
  960180, 960182,                                                                                                                              
  990145, and                                                                                                                                  
  990757                                                                                                                                       

  N = Number of                                                                                                                                
  subjects who                                                                                                                                 
  were randomized                                                                                                                              
  and received at                                                                                                                              
  least 1 dose of                                                                                                                              
  study drug                                                                                                                                   

  m = Number of                                                                                                                                
  evaluable                                                                                                                                    
  subjects with                                                                                                                                
  non-missing                                                                                                                                  
  baseline and                                                                                                                                 
  post-baseline                                                                                                                                
  WHOTOX grades                                                                                                                                

  \% = (n/m) x                                                                                                                                 
  100                                                                                                                                          

  ^a^ Includes                                                                                                                                 
  AST, ALT,                                                                                                                                    
  Alkaline                                                                                                                                     
  Phosphatase,                                                                                                                                 
  and Total                                                                                                                                    
  Bilirubin                                                                                                                                    

  ^b^ Includes                                                                                                                                 
  BUN and                                                                                                                                      
  Creatinine                                                                                                                                   
  --------------- ------------ --------------- --------- ------- -- ---------- ------- -- ------- ------- -- ------ ------- -- ------- ------- --

####### Neutrophils {#neutrophils .FlushLeftBold .unnumbered}

Among the 2103 evaluable anakinra-treated subjects, 6 (0.29%) were
observed to have at least 1 Grade 3 (\<0.98 x 10^9^/L) neutropenia. None
of the anakinra subjects reported a Grade 4 neutropenia. No Grade 3 or 4
neutropenia cases were observed among the 736 evaluable subjects
receiving placebo.

Table 4-41 lists the subjects with one or more Grade 3 or Grade 4
neutropenia laboratory values for the 5 randomized, placebo-controlled
trials. Assuming a lower limit of normal of 2 x 10^9^/L, 3 of 6 subjects
(50%) had a low baseline ANC. The median time to onset of the
neutropenic event is 71 days, and the median duration is 6 days (based
on the 5 cases for which data are available).

Three of 6 subjects (50.0%) were withdrawn due to the event and 5 of 6
subjects (83.3%) had a last available ANC value above the lowest value.
One subject experienced a lower respiratory infection and a second
subject experienced conjunctivitis and a tooth infection during the
period of neutropenia. Neutrophil counts recovered in 2 of the 3
subjects who continued on anakinra therapy, and follow-up ANC values are
not available for the third subject. Four of the 6 subjects who
experienced neutropenia were concomitantly receiving MTX, which may have
contributed to the events.

Of note is that in the large Safety Study (990757) and the Confirmatory
Efficacy Study (990145), in which subjects received anakinra at the
recommended dose of 100 mg daily for 24 weeks, only 1 of 1366 subjects
(0.07%; in Safety Study \[990757\]) had a decrease in ANC to Grade 3.

No SAEs of granulocytopenia or neutropenia have been reported in the
time period covered by this analysis. One subject in the large Safety
Study (990757), who died following upper gastrointestinal hemorrhage,
also had reported SAEs of renal failure, nausea, malaise, esophagitis,
duodenitis, depression, exacerbation of RA, and leukopenia.

It should be noted that 2 neutropenia cases were also observed (1 each)
in studies 0501 and 0502. In study 0501 a Grade 3 neutropenia was
observed in a Caucasian woman of unknown age receiving 6 mg/kg of
anakinra. Assuming a lower limit of normal of\
2 x 10^9^/L, this subject had a baseline ANC below normal (1.76 x
10^9^/L). In addition, 1 subject (in study 0502) had Grade 4 neutropenia
(\< 0.5 x 10^9^/L). This subject, a 58-year old Caucasian woman, entered
the study with neutropenia (1.026 x 10^9^/L), received a dose of 4 mg/kg
anakinra SC for 1 day. After a washout period of 46 days, 10 daily doses
of 1.0 mg/kg anakinra were administered, after which the subject was
withdrawn from study due to neutropenia. A liver-spleen scan indicated a
slightly enlarged spleen. She also had very high baseline rheumatoid
factor levels (2070 IU/mL; normal 0-30) and high IgM levels (1070 mg/dL;
normal 63-277). Although not indicated by the investigator, the subject
may have had Felty syndrome, a disease sometimes seen in subjects with
RA, and associated with neutropenia. During the trial the subject's
lowest ANC was 0.270 x 10^9^/L, 1 day after discontinuing 10 days of
dosing, and 11 days later was 0.406 x 10^9^/L.

Table 4‑41. By Subject Listing Of All Grade 3 or 4 Neutropenia Cases In
All RA Studies

<table style="width:100%;">
<colgroup>
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 15%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Study</td>
<td>Age</td>
<td>Sex</td>
<td><p>MTX</p>
<p>Use</p></td>
<td>Dose</td>
<td>Time to 1<sup>st</sup> Gr. 3/4 event (days)*</td>
<td>Baseline ANC</td>
<td>Lowest ANC</td>
<td>Duration of Grade 3 ANC* (days)</td>
<td>Last available ANC</td>
<td>Recovered while on anakinra?</td>
<td><p>Comments</p>
<p>(withdrawn, infections)</p></td>
</tr>
<tr class="even">
<td>960180</td>
<td>63</td>
<td>Male</td>
<td>Yes</td>
<td>0.4 mg/kg</td>
<td>24</td>
<td>1.73</td>
<td>0.96</td>
<td>4</td>
<td>1.48</td>
<td>No</td>
<td>Withdrawn</td>
</tr>
<tr class="odd">
<td>960180</td>
<td>63</td>
<td>Female</td>
<td>Yes</td>
<td>0.04 mg/kg</td>
<td>148</td>
<td>1.74</td>
<td>0.90</td>
<td>23</td>
<td>2.71</td>
<td>No</td>
<td>Withdrawn</td>
</tr>
<tr class="even">
<td>960180</td>
<td>62</td>
<td>Female</td>
<td>Yes</td>
<td>0.4 mg/kg</td>
<td>88</td>
<td>2.94</td>
<td>0.56</td>
<td>Unknown</td>
<td>0.56</td>
<td>No</td>
<td>Tooth infection, eye infection and oral ulcers</td>
</tr>
<tr class="odd">
<td>0560</td>
<td>52</td>
<td>Female</td>
<td>No</td>
<td>75 mg</td>
<td>57</td>
<td>2.35</td>
<td>0.95</td>
<td>4</td>
<td>2.27</td>
<td>Yes</td>
<td></td>
</tr>
<tr class="even">
<td>0560</td>
<td>62</td>
<td>Male</td>
<td>No</td>
<td>150 mg</td>
<td>8</td>
<td>1.90</td>
<td>0.91</td>
<td>9</td>
<td>1.06</td>
<td>Yes</td>
<td>Chest infection</td>
</tr>
<tr class="odd">
<td>990757</td>
<td>58</td>
<td>Female</td>
<td>Yes</td>
<td>100 mg</td>
<td>85</td>
<td>2.53</td>
<td>0.79</td>
<td>6</td>
<td>1.53</td>
<td>No</td>
<td>Withdrawn</td>
</tr>
<tr class="even">
<td colspan="12"></td>
</tr>
<tr class="odd">
<td colspan="12">*Best estimate from available data</td>
</tr>
<tr class="even">
<td colspan="12"></td>
</tr>
<tr class="odd">
<td
colspan="12">/stat/il1ra/fda_brfpkg/anlaysis/safety/statfiles/listings/l_lab_whotox34_hneuta.doc
(generated 12JUL2001)</td>
</tr>
<tr class="even">
<td colspan="12">Source:
/stat/il1ra/fda_brfpkg/anlaysis/safety/statfiles/listings/l_lab_whotox34_hneuta.lst</td>
</tr>
</tbody>
</table>

####### Lymphocytes {#lymphocytes .FlushLeftBold .unnumbered}

In the 5 randomized placebo-controlled studies, Grade 2 and 3
lymphopenia occurred at relatively similar incidence in anakinra and
placebo subjects.

Grade 3 lymphopenia was reported in 50 subjects: 17 (2.3%) placebo and
33 (1.6%) anakinra subjects.

Six cases of Grade 4 lymphopenia were seen in the anakinra groups. On
further evaluation 2 were noted as laboratory or data errors.

####### Eosinophils {#eosinophils .FlushLeftBold .unnumbered}

Two subjects (100 mg anakinra) had Grade 3 eosinophilia. The highest
values were 3.2  and 3.7 x 10^9^/L. Both subjects had no serious events,
and both continued on study.

#### Summary of Laboratory Findings

Changes in the mean values were observed for white blood count,
neutrophils, platelets and hemoglobin. For each of hematology parameter,
the mean values changed towards the midpoint of the reference range. One
interpretation of the mean changes in hematological parameters may be
that inhibition of excess IL-1 activity in RA patients helps "normalize"
the abnormalities often observed in patients with RA. Laboratory
abnormalities, such as Grade 3 or 4 neutropenia, were rare, often
occurring in subjects with baseline abnormalities or taking
myelosuppressive drugs such as MTX. In the majority of instances these
events were not of serious clinical consequence. There is no evidence
that anakinra is nephrotoxic or hepatotoxic, or that treatment with
anakinra is associated with abnormalities of routine serum chemistry
analytes or urinalysis.

### Antibodies

Serum samples from several studies were assayed for the presence of
anti-anakinra antibodies. The assay methods used to detect these
antibodies have evolved as the program has progressed. The earlier
studies, the Monotherapy Study and its extension (0560, and 0564/0564E1)
used an ELISA detecting IgG antibodies. Serum samples were considered
seroreactive for the formation of antibodies capable of binding to
anakinra if the optical density of the sample was 2-fold greater than
the optical density of pre-dose sample. For the MTX Combination Study
and its extension (960180, 960181) and the Low Dose Monotherapy Study
(960182), the ELISA was used in conjunction with a BIAcore 3000
confirmatory assay. For these studies, samples were considered
seroreactive by ELISA if binding was greater than a threshold defined as
baseline + 2x standard deviation obtained from pre-dose samples.
Seroreactive samples were then analyzed by both BIAcore and bioassay.
The samples from the Safety Study (990757) were analyzed by ELISA and
reactive samples further analyzed by BIAcore. The ELISA has been
modified throughout the program to improve sensitivity and reduce
background binding. A bioassay was used to determine whether the
detected antibodies were capable of neutralizing the biological effect
of anakinra in a cell-based assay. A monkey kidney epithelial cell line
(COS-1 cells), which produces IL-8 upon treatment with IL-1beta was
utilized for this purpose.

The percentage of subjects who were positive at one or more time points
ranged from 3.8% to 57.2% across studies (Table 4-42). However, 0.2% to
29.1% of subjects were positive at 2 or more time points. The antibodies
were rarely positive in the neutralizing bioassay (10/1303 subjects,
0.8%) and, of particular importance, antibody presence was transient,
because none of the subjects tested remained positive at subsequent time
points. The adverse event and treatment response profiles of the 9
subjects from the Safety Study (990757) who were positive in the
bioassay were indistinguishable from the rest of the subject population.
The increased incidence of observed binding antibodies in the Safety
Study (990757) is likely the result of incremental improvements in the
initial ELISA screening assay to detect lower affinity antibodies.
Considering the low incidence of neutralizing antibodies from this
study, and the transient nature of most of these antibodies, it is not
likely that previous studies failed to detect important neutralizing
antibodies.

In summary, while some subjects had evidence of anti-anakinra
antibodies, the appearance of potentially neutralizing antibodies was
transient in all cases and of no clinical significance.

Table 4‑42. Summary of Seropositivity Data in RA Studies

+--------------------+----+------+------+-------+---+--------+-------+
|                    |    | Imm  |      |       | B |        |       |
|                    |    | unoa |      |       | i |        |       |
|                    |    | ssay |      |       | o |        |       |
|                    |    |      |      |       | a |        |       |
|                    |    |      |      |       | s |        |       |
|                    |    |      |      |       | s |        |       |
|                    |    |      |      |       | a |        |       |
|                    |    |      |      |       | y |        |       |
+--------------------+----+------+------+-------+---+--------+-------+
|                    | Su | Posi | Posi | Pos   |   | Po     | Pos   |
|                    | bj | tive | tive | itive |   | sitive | itive |
|                    | ec | at 1 | at 2 | at    |   | at 1   | at    |
|                    | ts | or   | or   | Last  |   | or     | Last  |
|                    | Te | More | More | Avai  |   | More   | Avai  |
|                    | st | Vi   | Vi   | lable |   | Visits | lable |
|                    | ed | sits | sits | Visit |   |        | Visit |
|                    |    |      |      |       |   | n (%)  |       |
|                    | N  | n    | n    | n (%) |   |        | n (%) |
|                    |    | (%)  | (%)  |       |   |        |       |
+--------------------+----+------+------+-------+---+--------+-------+
| Studies 0560,      | 4  | 21   | 10   | 2     |   | 0      | 0     |
| 0564, 0564E1       | 12 | (5   | (2   | (     |   | (0.0%) | (     |
|                    |    | .1%) | .5%) | 0.5%) |   |        | 0.0%) |
+--------------------+----+------+------+-------+---+--------+-------+
| Studies 960180,    | 3  | 14   | 1    | 5     |   | 1      | 0     |
| 960181             | 51 | (4   | (0   | (     |   | (0.3%) | (     |
|                    |    | .0%) | .2%) | 1.4%) |   |        | 0.0%) |
+--------------------+----+------+------+-------+---+--------+-------+
| Study 960182       | 1  | 4    | 1    | 4     |   | 0      | 0     |
|                    | 04 | (3   | (1   | (     |   | (0.0%) | (     |
|                    |    | .8%) | .0%) | 3.8%) |   |        | 0.0%) |
+--------------------+----+------+------+-------+---+--------+-------+
| Study 990757       | 8  | 459  | 233  | 396   |   | 9      | 0/    |
|                    | 02 | (57  | (29  | (4    |   | /436\* | 436\* |
|                    |    | .2%) | .1%) | 9.4%) |   | (2.1%) | (     |
|                    |    |      |      |       |   |        | 0.0%) |
+--------------------+----+------+------+-------+---+--------+-------+
| Combined           | 16 | 498  | 245  | 407   |   | 10/    | 0/1   |
|                    | 69 | (29  | (14  | (2    |   | 1303\* | 303\* |
|                    |    | .8%) | .7%) | 4.4%) |   | (0.8%) | (     |
|                    |    |      |      |       |   |        | 0.0%) |
+--------------------+----+------+------+-------+---+--------+-------+
| \% = n/N x 100     |    |      |      |       |   |        |       |
|                    |    |      |      |       |   |        |       |
| n = number of      |    |      |      |       |   |        |       |
| subjects positive  |    |      |      |       |   |        |       |
| in the assay       |    |      |      |       |   |        |       |
|                    |    |      |      |       |   |        |       |
| \*All available    |    |      |      |       |   |        |       |
| assay results      |    |      |      |       |   |        |       |
+--------------------+----+------+------+-------+---+--------+-------+

### Anakinra Combination With Etanercept: Study 20000125

In a 24-week open-label, single-arm, safety study (20000125), subjects
who were receiving treatment with etanercept (Immunex Corp., USA) were
treated concomitantly with anakinra (1 mg/kg/day SC). A total of 58
subjects who had been receiving 25 mg SC twice-weekly etanercept therapy
for an average of 1.2 years, but still had residual disease (mean
tender/painful joint count 26.4, swollen joint count 17.4), were
enrolled. These subjects had RA for an average of 11.9 years. The
primary purpose of the study was to determine whether anakinra could be
used safely in subjects receiving standard etanercept therapy.

There were no deaths during the study. Seven subjects (12.1%) had SAEs
over the course of the study: injury/accidental electrocution (1),
withdrawal syndrome from combination opiates and barbiturates, along
with possible sertraline toxicity (1), gastric ulcer hemorrhage (1),
pneumonia (2 cases), and cellulitis (2 cases).

The most common adverse events were ISRs, experienced by 83% of the
subjects. The only other events reported by at least 10% of subjects
were URI (31%), RA flare (16%), and headache (12%).

Infections were reported by 48% of subjects (compared with 39% in the
anakinra group in the 5 randomized, placebo-controlled studies; Table
4-28). The most common was URI (13 subjects, 22%) followed by
influenza-like symptoms and urinary tract infection, each in 4 subjects
(7%). Most infections were considered mild to moderate, with 2 severe
infections reported: cellulitis and urinary tract infection (a
non-serious event). Four subjects (6.9%) reported serious infectious
episodes: cellulitis (2) and pneumonia (2). Of the 4 serious infections,
the 2 subjects experiencing cellulitis had been exposed to etanercept
for 112 and 184 days prior to initiation of anakinra treatment. Of the 2
subjects with pneumonia, prior etanercept exposure was 530 days and 1134
days. Three of the 4 subjects with serious infections were also
receiving corticosteroid medications. Of the subjects who had
infections, 61% of subjects received corticosteroids; 37% who did not
experience infections were receiving corticosteroids. Thus, it may be
possible that corticosteroid medications increase the risk of infections
among subjects treated with the combination of anakinra and etanercept.
No opportunistic infections were reported during this study.

It is possible that combination therapy with anakinra and etanercept
increases the risk of infection compared with anakinra alone.

Eleven subjects (19%) withdrew from the study because of adverse events.
Three of these were for serious infections mentioned above and a fourth
was withdrawn due to URI. Two were withdrawn due to ISRs, and 1 each due
to fatigue, worsening of RA, myalgia, cutaneous vasculitis, and
depression.

No Grade 3 or 4 neutropenia was observed during the study. One subject
had worsening to Grade 3 lymphopenia (the subject was hospitalized for
pneumonia). No other Grade 3 laboratory abnormalities were observed.

Even though efficacy was not formally evaluated in this study, changes
from baseline in selected components of the ACR score were assessed. The
results for all treated subjects are summarized in Table 4-43. The
completers analysis confirms these encouraging results, showing
improvement in all parameters.

Table 4‑43. Summary of Mean Disease Activity Measures in Study 20000125\
All Treated Subjects

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 4%" />
<col style="width: 11%" />
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 6%" />
<col style="width: 12%" />
<col style="width: 6%" />
<col style="width: 11%" />
<col style="width: 6%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4">Joint Counts</td>
<td colspan="2"></td>
<td colspan="4">Laboratory Parameters</td>
</tr>
<tr class="even">
<td>Visit Week</td>
<td colspan="2">Tender/Painful Joint Count</td>
<td colspan="2">Swollen Joint Count</td>
<td colspan="2">Health Assessment Questionnaire</td>
<td colspan="2">C-Reactive Protein (mg/dL)</td>
<td colspan="2">Erythrocyte Sedimentation Rate (mm/hr)</td>
</tr>
<tr class="odd">
<td></td>
<td>N</td>
<td>Mean (SD)</td>
<td>N</td>
<td>Mean (SD)</td>
<td>N</td>
<td>Mean (SD)</td>
<td>N</td>
<td>Mean (SD)</td>
<td>N</td>
<td>Mean (SD)</td>
</tr>
<tr class="even">
<td>Baseline</td>
<td>58</td>
<td>26.4 (14.0)</td>
<td>58</td>
<td>17.4 (7.3)</td>
<td>58</td>
<td>1.2 (0.7)</td>
<td>56</td>
<td>2.2 (2.8)</td>
<td>55</td>
<td>25.1 (24.9)</td>
</tr>
<tr class="odd">
<td>Week 2</td>
<td>58</td>
<td>22.4 (13.1)</td>
<td>58</td>
<td>14.7 (8.4)</td>
<td>58</td>
<td>1.1 (0.7)</td>
<td>58</td>
<td>1.3 (1.8)</td>
<td>55</td>
<td>20.6 (24.7)</td>
</tr>
<tr class="even">
<td>Week 12</td>
<td>45</td>
<td>20.8 (16.0)</td>
<td>45</td>
<td>10.8 (8.1)</td>
<td>45</td>
<td>1.0 (0.7)</td>
<td>44</td>
<td>0.9 (1.6)</td>
<td>43</td>
<td>14.6 (15.7)</td>
</tr>
<tr class="odd">
<td>Week 24</td>
<td>39</td>
<td>18.7 (15.8)</td>
<td>39</td>
<td>9.6 (9.3)</td>
<td>39</td>
<td>1.0 (0.7)</td>
<td>39</td>
<td>1.6 (2.6)</td>
<td>38</td>
<td>19.3 (20.9)</td>
</tr>
<tr class="even">
<td colspan="11"><p>N = number of subjects evaluable.</p>
<p>SD = standard deviation</p></td>
</tr>
</tbody>
</table>

### Overall Adverse Event Profile

#### Randomized, Placebo-controlled Trials

An overview of the subject incidence of adverse events, including SAEs,
serious infections, deaths and withdrawals for the 5 randomized,
placebo-controlled studies is shown in Table 4-44.

Injection site reactions occur more commonly among anakinra-treated
subjects, in a dose-dependent manner, than among placebo-treated
subjects, and these events account for the differences in subject
incidences of total adverse events between groups. The subject incidence
of SAEs is 8.4%, 7.1% and 12.2% in subjects receiving \< 100 mg, 100 mg
and \> 100 mg anakinra, respectively, compared to 6.5% in placebo
subjects. Serious infectious episodes occurred in 1.7% anakinra subjects
compared with 0.7% in placebo subjects. Six (0.3%) deaths in the
anakinra group, and 1 death (0.1%) in the placebo group were reported in
the 5 randomized, placebo-controlled studies. The treatment assignment
for an additional death reported in the Confirmatory Efficacy Study
(990145) remains blinded. The subject incidence of withdrawals due to
adverse events is similar among the groups, with a higher incidence in
the \> 100 mg group.

Table 4‑44. Safety Overview (Crude Subject Incidence) for
Placebo-controlled Studies

+-----------------------+---+----+--------+--------+--------+--------+
|                       |   |    | An     |        |        |        |
|                       |   |    | akinra |        |        |        |
|                       |   |    | (mg)   |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
|                       | P |    | \< 100 | 100    | \> 100 | All    |
|                       | l |    |        |        |        |        |
|                       | a |    |        |        |        |        |
|                       | c |    |        |        |        |        |
|                       | e |    |        |        |        |        |
|                       | b |    |        |        |        |        |
|                       | o |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| n (%)                 | ( |    | (N =   | (N =   | (N =   | (N =   |
|                       | N |    | 610)   | 1367)  | 196)   | 2173)  |
|                       | = |    |        |        |        |        |
|                       | 7 |    |        |        |        |        |
|                       | 5 |    |        |        |        |        |
|                       | 9 |    |        |        |        |        |
|                       | ) |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| Any adverse event     | 6 |    | 538    | 1254   | 190    | 1982   |
|                       | 4 |    | (88.2) | (91.7) | (96.9) | (91.2) |
|                       | 5 |    |        |        |        |        |
|                       | ( |    |        |        |        |        |
|                       | 8 |    |        |        |        |        |
|                       | 5 |    |        |        |        |        |
|                       | . |    |        |        |        |        |
|                       | 0 |    |        |        |        |        |
|                       | ) |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
|                       |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| Adverse event         | 6 |    | 491    | 1088   | 169    | 1748   |
| excluding ISR         | 2 |    | (80.5) | (79.6) | (86.2) | (80.4) |
|                       | 3 |    |        |        |        |        |
|                       | ( |    |        |        |        |        |
|                       | 8 |    |        |        |        |        |
|                       | 2 |    |        |        |        |        |
|                       | . |    |        |        |        |        |
|                       | 1 |    |        |        |        |        |
|                       | ) |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
|                       |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| Serious adverse event | 4 |    | 51     | 97     | 24     | 172    |
|                       | 9 |    | (8.4)  | (7.1)  | (12.2) | (7.9)  |
|                       | ( |    |        |        |        |        |
|                       | 6 |    |        |        |        |        |
|                       | . |    |        |        |        |        |
|                       | 5 |    |        |        |        |        |
|                       | ) |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
|                       |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| Serious infectious    | 5 |    | 7      | 25     | 4      | 36     |
| episode               | ( |    | (1.1)  | (1.8)  | (2.0)  | (1.7)  |
|                       | 0 |    |        |        |        |        |
|                       | . |    |        |        |        |        |
|                       | 7 |    |        |        |        |        |
|                       | ) |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
|                       |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| Death^a^              | 1 |    | 1      | 4      | 1      | 6      |
|                       | ( |    | (0.2)  | (0.3)  | (0.5)  | (0.3)  |
|                       | 0 |    |        |        |        |        |
|                       | . |    |        |        |        |        |
|                       | 1 |    |        |        |        |        |
|                       | ) |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
|                       |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| Withdrawal due to AE  | 8 |    | 58     | 186    | 36     | 280    |
|                       | 8 |    | (9.5)  | (13.6) | (18.4) | (12.9) |
|                       | ( |    |        |        |        |        |
|                       | 1 |    |        |        |        |        |
|                       | 1 |    |        |        |        |        |
|                       | . |    |        |        |        |        |
|                       | 6 |    |        |        |        |        |
|                       | ) |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| Includes studies      |   |    |        |        |        |        |
| 0560, 960180, 960182, |   |    |        |        |        |        |
| 990145, and 990757    |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| N = Number of         |   |    |        |        |        |        |
| randomized subjects   |   |    |        |        |        |        |
| who received at least |   |    |        |        |        |        |
| 1 dose of study drug  |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| n = Number of         |   |    |        |        |        |        |
| subjects reporting at |   |    |        |        |        |        |
| least 1 occurrence of |   |    |        |        |        |        |
| an adverse event      |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| \% = (n/N) x 100      |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| ^a^Excludes 1 death   |   |    |        |        |        |        |
| in study 990145 due   |   |    |        |        |        |        |
| to blinded data       |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+
| /stat/il1             |   |    |        |        |        |        |
| ra/fda_brfpkg/analysi |   |    |        |        |        |        |
| s/safety/statfiles/ta |   |    |        |        |        |        |
| bles/t_ae_overall.sas |   |    |        |        |        |        |
|                       |   |    |        |        |        |        |
| Output:               |   |    |        |        |        |        |
| t                     |   |    |        |        |        |        |
| _ae_overall_crude.rtf |   |    |        |        |        |        |
| (generated 13JUN2001) |   |    |        |        |        |        |
+-----------------------+---+----+--------+--------+--------+--------+

#### All RA Studies

The exposure-adjusted adverse event rates reported in the all RA studies
are shown in Table 4-45. The event rates for the placebo and anakinra
groups from the 5 randomized, placebo-controlled studies are included
for reference.

Table 4‑45. Safety Overview (Exposure-adjusted Event Incidence)\
for Placebo-controlled and All Studies

+---------------------------+-----------+--------------+---+-----------+
|                           | Placebo-c |              |   | All       |
|                           | ontrolled |              |   | S         |
|                           | S         |              |   | tudies^b^ |
|                           | tudies^a^ |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
|                           | Placebo   | Anakinra     |   | Anakinra  |
+---------------------------+-----------+--------------+---+-----------+
| n (rate per patient year) | (N = 759) | (N = 2173)   |   | (N =      |
|                           |           |              |   | 2531)     |
+---------------------------+-----------+--------------+---+-----------+
| Any adverse event^c^      | 2750      | 10752        |   | 15297     |
|                           | (9.284)   | (12.724)     |   | (9.392)   |
+---------------------------+-----------+--------------+---+-----------+
|                           |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| Adverse event excluding   | 2410      | 7262 (8.594) |   | 11293     |
| ISR^c^                    | (8.136)   |              |   | (6.934)   |
+---------------------------+-----------+--------------+---+-----------+
|                           |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| Serious adverse event     | 72        | 288 (0.341)  |   | 616       |
|                           | (0.243)   |              |   | (0.329)   |
+---------------------------+-----------+--------------+---+-----------+
|                           |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| Serious infectious        | 6 (0.020) | 46 (0.054)   |   | 110       |
| episode                   |           |              |   | (0.059)   |
+---------------------------+-----------+--------------+---+-----------+
|                           |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| Death per 100 patient     | 1 (0.338) | 6 (0.710)    |   | 13        |
| years^d^                  |           |              |   | (0.694)   |
+---------------------------+-----------+--------------+---+-----------+
|                           |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| Withdrawal due to AE      | 119       | 514 (0.608)  |   | 692       |
|                           | (0.402)   |              |   | (0.369)   |
+---------------------------+-----------+--------------+---+-----------+
| ^a^Includes studies 0560, |           |              |   |           |
| 960180, 960182, 990145,   |           |              |   |           |
| and 990757                |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| ^b^Includes studies 0505, |           |              |   |           |
| 0512, 0560, 0564, 0564E1, |           |              |   |           |
| 0564E2, 0564E3, 960180,   |           |              |   |           |
| 960181, 960182, 970102,   |           |              |   |           |
| 980220, 990145, and       |           |              |   |           |
| 990757                    |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| N = Number of randomized  |           |              |   |           |
| subjects who received at  |           |              |   |           |
| least 1 dose of study     |           |              |   |           |
| drug                      |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| n = Number of adverse     |           |              |   |           |
| events                    |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| rate = n/(sum of patient  |           |              |   |           |
| years of exposure).       |           |              |   |           |
| Patient year of exposure  |           |              |   |           |
| is the duration between   |           |              |   |           |
| the first dose date and   |           |              |   |           |
| the last dose date        |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| ^c^Excludes studies       |           |              |   |           |
| 0564E2, 0564E3 and 970102 |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| ^d^Excludes 1 death in    |           |              |   |           |
| study 990145 due to       |           |              |   |           |
| blinded data              |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+
| /sta                      |           |              |   |           |
| t/il1ra/fda_brfpkg/analys |           |              |   |           |
| is/safety/statfiles/table |           |              |   |           |
| s/t_ae_overall_rctall.sas |           |              |   |           |
|                           |           |              |   |           |
| Output:                   |           |              |   |           |
| t_ae_overall_rctall.rtf   |           |              |   |           |
| (generated 13JUN2001)     |           |              |   |           |
+---------------------------+-----------+--------------+---+-----------+

The rates of any adverse event (with or without ISRs), SAEs, serious
infectious events, and deaths are similar for the all-studies anakinra
group compared with the anakinra group from the 5 randomized,
placebo-controlled studies. The rate of withdrawals due to adverse
events is lower in the all-studies anakinra group compared with the 5
randomized, placebo-controlled studies anakinra group, possibly due to
lower withdrawal rate due to ISRs later in the study phases.

### Summary of Safety

The safety database with anakinra in the treatment of subjects with RA
is extensive: 2531 subjects received at least 1 dose of anakinra and the
total exposure is 1872.9 patient-years (excludes clinical pharmacology
studies). At the recommended dose of 100 mg SC anakinra daily, 1367
subjects have received at least 1 dose, and the total exposure is 559.6
patient-years.

The incidence of mortality is 0.4% in both the placebo and anakinra
groups in the large Safety Study (990757), and only 1 death (treatment
assignment blinded) occurred in the 24-week phase for the Confirmatory
Efficacy Study (990145; N = 501). It is not unexpected that the deaths
in the remaining RA studies occurred mostly in anakinra subjects,
because of the 17.2-fold greater duration of exposure between anakinra
and placebo in these studies.

The subject incidence of SAEs at the 100 mg/day anakinra dose is low
(7.1% compared with 6.5% in placebo group). Serious infectious episodes
occur in 1.8% of 100 mg/day anakinra subjects and 0.7% of placebo
subjects. The most common serious infectious event at a 100 mg/day
anakinra is pneumonia (0.7%). The risk of experiencing a serious
infection appeared to be higher in subjects receiving corticosteroid
treatment, and in subjects with a history of asthma or pneumonia. There
were no cases of tuberculosis or opportunistic infections reported.

Of interest, in the sepsis indication, the mortality rate in 3 anakinra
trials where subjects received a mean dose of anakinra up to 34.7 times
higher than the recommended daily dose for RA (100 mg), is numerically
lower than the placebo mortality rate (anakinra 30.6%, placebo 35.5%).
These findings suggest that anakinra does not severely impair the
ability to respond to serious bacterial infections.

When data from all RA studies are considered, there is no indication
that anakinra is associated with an increased risk of malignancy (16
observed malignancies compared with 15.6 expected based on the National
Cancer Institute's SEER statistics). Exposure-adjusted malignancy rates
per 100 patient-years of study drug exposure are 1.2 for anakinra and
2.0 for placebo subjects.

ISRs were the only adverse event clearly associated with anakinra
treatment, occurring in 64% of anakinra subjects compared to 27% of
placebo subjects. ISRs occur more commonly among women. The most common
reason for withdrawal is ISRs, occurring in 5.6% of anakinra subjects.
Of the subjects who experienced ISRs in the 5 randomized,
placebo-controlled studies, 95.3% of them had mild or moderate ISRs.
Worsening of RA occurred more frequently in placebo subjects. In earlier
studies, a few subjects were withdrawn due to protocol-specified
criteria for neutropenia or leukopenia. Grade 3 or 4 neutropenia
occurred rarely at the 100 mg anakinra dose (0.07%) and did not result
in serious clinical sequelae. Anakinra treatment is associated with a
slight mean decrease in neutrophil and platelet counts within the normal
range, consistent with its biological effect of reducing inflammation.
No severe cases of thrombocytopenia have been observed. Grade 4
lymphopenia occurred only in subjects with Grade 2 or 3 baseline
abnormalities. There is a slight improvement in anemia. Also, there is
no evidence of hepatic or renal toxicity, and no trends of abnormalities
in routine serum chemistry analytes or urinalysis.

In general, the adverse event profile is similar in male and female
subjects, as well as in younger (\< 65 years) and older (≥  65 years)
subjects.

Although some subjects had evidence of anti-anakinra antibodies, the
appearance of potentially neutralizing antibodies was transient in all
cases, indicating that anakinra can be administered chronically.

Lastly, though experience is limited, concomitant use of anakinra with
etanercept may result in improvement of RA signs and symptoms among some
subjects. It is possible that the combination increases the risk of
infections as compared with anakinra alone.

The 100 mg/day anakinra dose, which was demonstrated to be effective in
treating subjects with RA, is preferred to a dose greater than 100 mg
based on the overall safety profile. In general, the subject incidence
of adverse events is higher in the \> 100 mg anakinra group compared
with placebo (see Table 4-44).

In conclusion, 100 mg/day SC anakinra was well tolerated by most
subjects and the safety profile, in conjunction with the efficacy
profile, indicate that anakinra will provide benefit to subjects
suffering from RA, a chronic debilitating disease.

# Risk/Benefit Assessment

Rheumatoid arthritis is a chronic autoimmune disease for which the goals
of therapy include:

-   Pain and inflammation relief

-   Control of disease progression (bone and cartilage destruction)

-   Halting or delaying systemic complications of RA

-   Ultimately, improving the quality and longevity of life of RA
    sufferers

While trying to accomplish these goals, health care providers must also
weigh the many side effects of various existing therapies, including
hepatotoxicity and an increased risk of infections and cancers.

As discussed in Section 3, RA is mediated by antigen-driven T cells and
macrophages which produce various cytokines, predominantly IL-1 and
tumor necrosis factor TNFα. Although there are a number of therapeutic
options available for RA, including TNF-specific inhibitors, a
substantial number of subjects either do not respond, or partially
respond to the existing therapies. In addition, responding subjects
often become refractory to or intolerant of these medications as their
disease progresses. For example, the most-widely used DMARD, MTX, has
been shown to improve the signs and symptoms of RA and retard structural
damage. However, use of MTX is often limited due to adverse effects and
tolerability issues.

Recently, a number of newly approved biological agents that specifically
target the proinflammatory cytokine TNFα have become available (ENBREL
and REMICADE). Anakinra represents the first RA therapy that
specifically inhibits the effects of IL-1, a pivotal proinflammatory
cytokine that mediates many cellular responses including those important
in synovial inflammation, proliferation of synoviocytes (pannus
formation), cartilage degradation, and osteoclast-mediated bone erosions
characteristic of RA. Anakinra, a recombinant form of interleukin-1
receptor antagonist (IL-1Ra), specifically targets the proinflammatory
effects of IL-1.

The results of the anakinra clinical development program indicate that
the benefits of anakinra therapy, alone or in combination with other
DMARDs, include:

-   Rapid and sustained improvement in ACR~20~

-   Improvement in ACR~50~ and ACR~70~

-   Reduction of radiographic disease progression

The risks of anakinra therapy observed in these studies include:

-   Injection site reactions

-   Possible slight increase in serious infectious episodes, mostly
    attributed to pneumonia

The data presented here clearly demonstrate the clinical benefits of
anakinra in RA trials. The positive effects of anakinra across these
trials are consistent with respect to the ACR~20~ results at 24 weeks,
the durability of those effects (sustained response), and the magnitude
of the effect achieved (ACR~50~, ACR~70~) at 24 weeks. Clinically
important benefits were seen when anakinra was used either as a
monotherapy or in combination with MTX. As predicted by the biology,
anakinra also demonstrates an important RA therapeutic benefit by
protecting bone and cartilage as seen on radiographic examination
(Larsen and modified Sharp scoring systems).

As discussed in Section 2 and Section 4.5 anakinra has been studied in
2606 subjects with RA (\~2000 patient-years experience), in a range of
therapeutic settings, including subjects at both early and later stages
of the disease and those receiving treatment with a variety of
antirheumatic drugs. Overall, data from the large safety database
provide support that anakinra is a well tolerated therapeutic for
patients with RA. Injection site reactions (ISRs) were the only clearly
identified adverse event associated with anakinra use. The majority of
ISRs were mild to moderate and well-tolerated by most subjects. Serious
infectious episodes are uncommon (1.7% in anakinra and 0.7% in placebo).
There is no evidence that subjects on anakinra therapy are at an
increased risk for malignancy.

Data from 5 randomized, placebo-controlled trials of anakinra in RA
subjects indicates anakinra is efficacious either alone or in
combination with other DMARDs.

The potential benefit of anakinra treatment outweighs the identified
risks, and supports the use of anakinra for the treatment of RA.
Anakinra's effects on the signs and symptoms of RA occur early, are
sustained and consistent. Additionally, preliminary radiographic data
demonstrate anakinra may retard structural damage. The drug is well
tolerated with the most common and consistently reported
treatment‑related adverse event being injection site reactions (ISRs).
The safety, efficacy and unique mechanism of action demonstrate that
anakinra offers RA patients a favorable risk/benefit profile.

## Proposed Indication

"Anakinra is indicated for the reduction in signs and symptoms of active
rheumatoid arthritis, in subjects 18 years of age or older. Anakinra can
be used alone or in combination with other disease-modifying
antirheumatic drugs (DMARDs)."

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```{=html}
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```
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Appendix 4- 1. Study 990145 -- Criteria for Lack of Efficacy Designation

Study 990145 incorporated the use of a special subject status
designation, Lack of Efficacy (LOE), with the objective of retaining
subjects in the study for evaluation of the radiographic endpoint when
they might otherwise withdraw from the study due to a flare in signs and
symptoms of RA. LOE assessments were conducted using a pre-defined
algorithm, which maintained the study blind regarding randomized
treatment assignments. Declaration of LOE on or after week 16 allowed
subjects to receive treatment with protocol-specified agents that could
alleviate the signs and symptoms of RA with minimal effects on
underlying structural damage.

***Definition of Lack of Efficacy***

-   Failure to meet the ACR~20~ criteria for improvement on the last
    three consecutive visits, on or after the Week 16 visit, beginning
    with the visit at which the LOE request is made.

-   ACR~20~ is defined as 20% improvement in tender and swollen joint
    count, and three out of the following five assessments:

1)  Subject assessment of disease activity

2)  Physician assessment of disease activity

3)  Subject assessment of pain

4)  Acute phase reactant: C-reactive protein

5)  HAQ

***LOE Determination***

-   The ACR~20~ will be calculated, by Amgen or it's designee, by
    comparing the current visit assessment and the two prior assessments
    against baseline. Site staff will forward the ACR assessments to
    Amgen via Federal Express. Determination of LOE will take
    approximately 3-5 working days, and site staff will be informed only
    whether or not a subject meets LOE.

***Changes in medications for subjects who meet LOE***

• If a subject meets the objective criteria for LOE they may first
obtain additional therapeutic treatment by optimizing their MTX,
corticosteroid and/or NSAID doses. Optimization of these medications can
be done based on the clinical judgment of the principal investigator,
and must be documented in the source document. The MTX dose cannot be
increased above 25 mg/wk.

• Subjects who optimize their dose of MTX, should wait at least 8 weeks
before seeking additional therapy.

• Once a subject has optimized their dose of MTX (either prior to
randomization or during the trial) and continues to manifest the
criteria for LOE, they can modify their background therapy through the
use of the medications listed below, however, they must continue to take
the randomized study drug: (additional DMARD therapy will not be
provided by Amgen Inc.). Additionally, the investigator may continue to
adjust the subject's DMARD therapy as needed, provided that adequate
time is allowed for the medication to become beneficial to the subject.
Amgen should be notified before the addition of a DMARD.

> A. hydroxychloroquine
>
> B. sulfasalazine
>
> C. gold
>
> D. minocycline
>
> E. cyclosporine

END App.4-1

Appendix 4- 2. Proportion of Patients Achieving an ACR~20~ Response at
Week 24 by Injection Site Reaction

**Study 0560\
Intent-to-Treat Population Using Non-Responder Imputation**

<table style="width:100%;">
<colgroup>
<col style="width: 3%" />
<col style="width: 28%" />
<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%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="8">Anakinra</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><p>Placebo</p>
<p>(N = 121)</p></td>
<td colspan="2"><p>30 mg</p>
<p>(N = 119)</p></td>
<td colspan="2"><p>75 mg</p>
<p>(N = 116)</p></td>
<td colspan="2"><p>150 mg</p>
<p>(N = 117)</p></td>
<td colspan="2"><p>All</p>
<p>(N = 352)</p></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>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">At Least One ISR</td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">30</td>
<td colspan="2">59</td>
<td colspan="2">85</td>
<td colspan="2">94</td>
<td colspan="2">238</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Number of Responders (%)</td>
<td>7</td>
<td>(23.3)</td>
<td>25</td>
<td>(42.4)</td>
<td>31</td>
<td>(36.5)</td>
<td>34</td>
<td>(36.2)</td>
<td>90</td>
<td>(37.8)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">2.42</td>
<td colspan="2">1.89</td>
<td colspan="2">1.86</td>
<td colspan="2">2.00</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>95% Confidence Interval</td>
<td></td>
<td></td>
<td colspan="2">(0.90, 6.51)</td>
<td colspan="2">(0.73, 4.90)</td>
<td colspan="2">(0.72, 4.79)</td>
<td colspan="2">(0.82, 4.85)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>p-value<sup>a</sup></td>
<td></td>
<td></td>
<td colspan="2">0.077</td>
<td colspan="2">0.188</td>
<td colspan="2">0.193</td>
<td colspan="2">0.120</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>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">No ISR</td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">91</td>
<td colspan="2">60</td>
<td colspan="2">31</td>
<td colspan="2">22</td>
<td colspan="2">113</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Number of Responders (%)</td>
<td>23</td>
<td>(25.3)</td>
<td>20</td>
<td>(33.3)</td>
<td>7</td>
<td>(22.6)</td>
<td>10</td>
<td>(45.5)</td>
<td>37</td>
<td>(32.7)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">1.48</td>
<td colspan="2">0.862</td>
<td colspan="2">2.46</td>
<td colspan="2">1.44</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>95% Confidence Interval</td>
<td></td>
<td></td>
<td colspan="2">(0.72, 3.02)</td>
<td colspan="2">(0.33, 2.27)</td>
<td colspan="2">(0.94, 6.46)</td>
<td colspan="2">(0.78, 2.66)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>p-value<sup>a</sup></td>
<td></td>
<td></td>
<td colspan="2">0.283</td>
<td colspan="2">0.764</td>
<td colspan="2">0.062</td>
<td colspan="2">0.245</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="13"><p>N = Number of patients randomized</p>
<p>n = Number of evaluable patients</p>
<p>Patients with non-evaluable ACR criteria are non-responders</p>
<p>p-value and confidence intervals are exact if expected cell
frequencies are less than 5</p></td>
</tr>
<tr class="even">
<td colspan="13"><p><em>Biostatistics: 10AUG1999</em></p>
<p><em>/stat/il1ra/i0560/analysis/final/statfiles/tables/acr20nr_0560_anyisr_xtabs.rtf</em></p></td>
</tr>
</tbody>
</table>

**Appendix 4-3. Proportion of Patients Achieving a Sustained ACR~20~
Response by Injection Site Reaction**

**Study 0560**

Intent-to-Treat Population Using Non-Responder Imputation

<table style="width:100%;">
<colgroup>
<col style="width: 3%" />
<col style="width: 28%" />
<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%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="8">Anakinra</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><p>Placebo</p>
<p>(N = 121)</p></td>
<td colspan="2"><p>30 mg</p>
<p>(N = 119)</p></td>
<td colspan="2"><p>75 mg</p>
<p>(N = 116)</p></td>
<td colspan="2"><p>150 mg</p>
<p>(N = 117)</p></td>
<td colspan="2"><p>All</p>
<p>(N = 352)</p></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>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">At Least One ISR</td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">30</td>
<td colspan="2">59</td>
<td colspan="2">85</td>
<td colspan="2">94</td>
<td colspan="2">238</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Number of Responders (%)</td>
<td>3</td>
<td>(10.0)</td>
<td>19</td>
<td>(32.2)</td>
<td>26</td>
<td>(30.6)</td>
<td>21</td>
<td>(22.3)</td>
<td>66</td>
<td>(27.7)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">4.28</td>
<td colspan="2">3.97</td>
<td colspan="2">2.59</td>
<td colspan="2">3.45</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>95% Confidence Interval</td>
<td></td>
<td></td>
<td colspan="2">(1.15, 15.87)</td>
<td colspan="2">(1.10, 14.25)</td>
<td colspan="2">(0.71, 9.38)</td>
<td colspan="2">(1.01, 11.77)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>p-value<sup>a</sup></td>
<td></td>
<td></td>
<td colspan="2">0.022</td>
<td colspan="2">0.026</td>
<td colspan="2">0.136</td>
<td colspan="2">0.036</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>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">No ISR</td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">91</td>
<td colspan="2">60</td>
<td colspan="2">31</td>
<td colspan="2">22</td>
<td colspan="2">113</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Number of Responders (%)</td>
<td>10</td>
<td>(11.0)</td>
<td>14</td>
<td>(23.3)</td>
<td>7</td>
<td>(22.6)</td>
<td>7</td>
<td>(31.8)</td>
<td>28</td>
<td>(24.8)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">2.47</td>
<td colspan="2">2.36</td>
<td colspan="2">3.78</td>
<td colspan="2">2.67</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>95% Confidence Interval</td>
<td></td>
<td></td>
<td colspan="2">(1.01, 5.99)</td>
<td colspan="2">(0.68, 7.71)</td>
<td colspan="2">(1.03, 12.97)</td>
<td colspan="2">(1.22, 5.84)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>p-value<sup>a</sup></td>
<td></td>
<td></td>
<td colspan="2">0.042</td>
<td colspan="2">0.134</td>
<td colspan="2">0.022</td>
<td colspan="2">0.012</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="13"><p>N = Number of patients randomized</p>
<p>n = Number of evaluable patients</p>
<p>Patients with non-evaluable ACR criteria are non-responders</p>
<p>p-value and confidence intervals are exact if expected cell
frequencies are less than 5</p></td>
</tr>
<tr class="even">
<td colspan="13"><p><em>Biostatistics: 10AUG1999</em></p>
<p><em>/stat/il1ra/i0560/analysis/final/statfiles/tables/acrsusnr_0560_anyisr_xtabs.rtf</em></p></td>
</tr>
</tbody>
</table>

Appendix 4-4. Study 960180 -- Individual ACR Components Change From
Baseline Lower Anakinra Doses
![](media/image37.wmf){width="8.819444444444445in"
height="5.738888888888889in"}

Appendix 4-5. Proportion of Patients Achieving an ACR~20~ Response at
Week 12 by Injection Site Reaction

**Study 960180**

**Intent-to-Treat Population Using Non-Responder Imputation**

<table>
<colgroup>
<col style="width: 2%" />
<col style="width: 26%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 3%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 2%" />
<col style="width: 6%" />
<col style="width: 2%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg/kg)</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><p>Placebo</p>
<p>(N = 74)</p></td>
<td colspan="2"><p>0.04</p>
<p>(N = 63)</p></td>
<td colspan="2"><p>0.1</p>
<p>(N = 74)</p></td>
<td colspan="2"><p>0.4</p>
<p>(N = 77)</p></td>
<td colspan="2"><p>1.0</p>
<p>(N = 59)</p></td>
<td colspan="2"><p>2.0</p>
<p>(N = 72)</p></td>
<td colspan="2"><p>All</p>
<p>(N = 345)</p></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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">At Least One ISR</td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">20</td>
<td colspan="2">12</td>
<td colspan="2">27</td>
<td colspan="2">43</td>
<td colspan="2">38</td>
<td colspan="2">45</td>
<td colspan="2">165</td>
</tr>
<tr class="even">
<td></td>
<td>Number of Responders (%)</td>
<td>4</td>
<td>(20.0)</td>
<td>1</td>
<td>(8.3)</td>
<td>9</td>
<td>(33.3)</td>
<td>12</td>
<td>(27.9)</td>
<td>14</td>
<td>(36.8)</td>
<td>18</td>
<td>(40.0)</td>
<td>54</td>
<td>(32.7)</td>
</tr>
<tr class="odd">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">0.364</td>
<td colspan="2">2.00</td>
<td colspan="2">1.55</td>
<td colspan="2">2.33</td>
<td colspan="2">2.67</td>
<td colspan="2">1.95</td>
</tr>
<tr class="even">
<td></td>
<td>95% C.I. for Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">(0.01, 4.49)</td>
<td colspan="2">(0.52, 7.77)</td>
<td colspan="2">(0.43, 5.58)</td>
<td colspan="2">(0.65, 8.38 )</td>
<td colspan="2">(0.77, 9.28)</td>
<td colspan="2">(0.62, 6.10)</td>
</tr>
<tr class="odd">
<td></td>
<td>p-value</td>
<td></td>
<td></td>
<td colspan="2">0.626</td>
<td colspan="2">0.312</td>
<td colspan="2">0.502</td>
<td colspan="2">0.188</td>
<td colspan="2">0.116</td>
<td colspan="2">0.247</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">No ISR</td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">54</td>
<td colspan="2">51</td>
<td colspan="2">47</td>
<td colspan="2">34</td>
<td colspan="2">21</td>
<td colspan="2">27</td>
<td colspan="2">180</td>
</tr>
<tr class="odd">
<td></td>
<td>Number of Responders (%)</td>
<td>10</td>
<td>(18.5)</td>
<td>15</td>
<td>(29.4)</td>
<td>17</td>
<td>(36.1)</td>
<td>7</td>
<td>(20.5)</td>
<td>13</td>
<td>(61.9)</td>
<td>9</td>
<td>(33.3)</td>
<td>61</td>
<td>(33.9)</td>
</tr>
<tr class="even">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">1.83</td>
<td colspan="2">2.49</td>
<td colspan="2">1.14</td>
<td colspan="2">7.15</td>
<td colspan="2">2.20</td>
<td colspan="2">2.26</td>
</tr>
<tr class="odd">
<td></td>
<td>95% C.I. for Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">(0.74, 4.57)</td>
<td colspan="2">(1.01, 6.19)</td>
<td colspan="2">(0.39, 3.35)</td>
<td colspan="2">(2.34, 21.84)</td>
<td colspan="2">(0.77, 6.31)</td>
<td colspan="2">(1.06, 4.79)</td>
</tr>
<tr class="even">
<td></td>
<td>p-value</td>
<td></td>
<td></td>
<td colspan="2">0.190</td>
<td colspan="2">0.046</td>
<td colspan="2">0.811</td>
<td colspan="2">0.001</td>
<td colspan="2">0.138</td>
<td colspan="2">0.031</td>
</tr>
<tr class="odd">
<td colspan="16">N = Number of patients randomized</td>
</tr>
<tr class="even">
<td colspan="16">n = Number of evaluable patients</td>
</tr>
<tr class="odd">
<td colspan="16">Patients with non-evaluable ACR criteria are
non-responders</td>
</tr>
<tr class="even">
<td colspan="16">p-value and confidence intervals are exact if expected
cell frequencies are less than 5</td>
</tr>
<tr class="odd">
<td colspan="16"><p><em>Biostatistics: 02AUG1999</em></p>
<p>/stat/il1ra/i960180abr/analysis/final/statfiles/tables/acr2012nr_960180_anyisr_xtabs</p></td>
</tr>
</tbody>
</table>

Appendix 4-6. Proportion of Patients Achieving an ACR~20~ Response at
Week 24 by Injection Site

**Study 960180**

**Intent-to-Treat Population Using Non-Responder Imputation**

<table style="width:100%;">
<colgroup>
<col style="width: 2%" />
<col style="width: 26%" />
<col style="width: 3%" />
<col style="width: 5%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 2%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg/kg)</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><p>Placebo</p>
<p>(N = 48)</p></td>
<td colspan="2"><p>0.04</p>
<p>(N = 63)</p></td>
<td colspan="2"><p>0.1</p>
<p>(N = 46)</p></td>
<td colspan="2"><p>0.4</p>
<p>(N = 55)</p></td>
<td colspan="2"><p>1.0</p>
<p>(N = 59)</p></td>
<td colspan="2"><p>2.0</p>
<p>(N = (46)</p></td>
<td colspan="2"><p>All</p>
<p>(N = 269)</p></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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">At Least One ISR</td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">13</td>
<td colspan="2">12</td>
<td colspan="2">14</td>
<td colspan="2">30</td>
<td colspan="2">38</td>
<td colspan="2">32</td>
<td colspan="2">126</td>
</tr>
<tr class="even">
<td></td>
<td>Number of Responders (%)</td>
<td>2</td>
<td>(15.4)</td>
<td>1</td>
<td>(8.3)</td>
<td>6</td>
<td>(42.9)</td>
<td>10</td>
<td>(33.3)</td>
<td>12</td>
<td>(31.6)</td>
<td>11</td>
<td>(34.4)</td>
<td>40</td>
<td>(31.8)</td>
</tr>
<tr class="odd">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">0.50</td>
<td colspan="2">4.13</td>
<td colspan="2">2.75</td>
<td colspan="2">2.54</td>
<td colspan="2">2.88</td>
<td colspan="2">2.56</td>
</tr>
<tr class="even">
<td></td>
<td>95% C.I. for Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">(0.01, 11.25)</td>
<td colspan="2">(0.52, 49.59)</td>
<td colspan="2">(0.45, 29.63)</td>
<td colspan="2">(0.44, 26.68)</td>
<td colspan="2">(0.48, 30.67)</td>
<td colspan="2">(0.52, 24.68)</td>
</tr>
<tr class="odd">
<td></td>
<td>p-value</td>
<td></td>
<td></td>
<td colspan="2">1.000</td>
<td colspan="2">0.209</td>
<td colspan="2">0.290</td>
<td colspan="2">0.472</td>
<td colspan="2">0.287</td>
<td colspan="2">0.344</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">No ISR</td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">35</td>
<td colspan="2">51</td>
<td colspan="2">32</td>
<td colspan="2">25</td>
<td colspan="2">21</td>
<td colspan="2">14</td>
<td colspan="2">143</td>
</tr>
<tr class="odd">
<td></td>
<td>Number of Responders (%)</td>
<td>9</td>
<td>(25.7)</td>
<td>11</td>
<td>(21.6)</td>
<td>8</td>
<td>(25.0)</td>
<td>10</td>
<td>(40.0)</td>
<td>13</td>
<td>(61.9)</td>
<td>5</td>
<td>(35.7)</td>
<td>47</td>
<td>(32.9)</td>
</tr>
<tr class="even">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">0.79</td>
<td colspan="2">0.96</td>
<td colspan="2">1.93</td>
<td colspan="2">4.69</td>
<td colspan="2">1.61</td>
<td colspan="2">1.41</td>
</tr>
<tr class="odd">
<td></td>
<td>95% C.I. for Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">(0.29, 2.18)</td>
<td colspan="2">(0.32, 2.90)</td>
<td colspan="2">(0.64, 5.80)</td>
<td colspan="2">(1.47, 15.01)</td>
<td colspan="2">(0.33, 7.19)</td>
<td colspan="2">(0.61, 3.26)</td>
</tr>
<tr class="even">
<td></td>
<td>p-value</td>
<td></td>
<td></td>
<td colspan="2">0.655</td>
<td colspan="2">0.946</td>
<td colspan="2">0.241</td>
<td colspan="2">0.007</td>
<td colspan="2">0.503</td>
<td colspan="2">0.414</td>
</tr>
<tr class="odd">
<td colspan="16">N = Number of patients participating in the 24-week
protocol</td>
</tr>
<tr class="even">
<td colspan="16">n = Number of evaluable patients</td>
</tr>
<tr class="odd">
<td colspan="16">Patients with non-evaluable ACR criteria are
non-responders</td>
</tr>
<tr class="even">
<td colspan="16">p-value and confidence intervals are exact if expected
cell frequencies are less than 5</td>
</tr>
<tr class="odd">
<td colspan="16">- : Due to zero events, statistics cannot be
calculated</td>
</tr>
<tr class="even">
<td colspan="16"><p><em>Biostatistics: 02AUG1999</em></p>
<p>/stat/il1ra/i960180abr/analysis/final/statfiles/tables/acr2024nr_960180_anyisr_xtabs</p></td>
</tr>
</tbody>
</table>

Appendix 4-7. Proportion of Patients Achieving a Sustained ACR~20~
Response by Injection Site Reaction

Study 960180

####### Intent-to-Treat Population Using Non-Responder Imputation {#intent-to-treat-population-using-non-responder-imputation .unnumbered}

<table style="width:100%;">
<colgroup>
<col style="width: 2%" />
<col style="width: 24%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 2%" />
<col style="width: 6%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 2%" />
<col style="width: 8%" />
<col style="width: 2%" />
<col style="width: 8%" />
<col style="width: 2%" />
<col style="width: 8%" />
<col style="width: 2%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg/kg)</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><p>Placebo</p>
<p>(N = 48)</p></td>
<td colspan="2"><p>0.04</p>
<p>(N = 63)</p></td>
<td colspan="2"><p>0.1</p>
<p>(N = 46)</p></td>
<td colspan="2"><p>0.4</p>
<p>(N = 55)</p></td>
<td colspan="2"><p>1.0</p>
<p>(N = 59)</p></td>
<td colspan="2"><p>2.0</p>
<p>(N = 46)</p></td>
<td colspan="2"><p>All</p>
<p>(N = 269)</p></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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">At Least One ISR</td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">13</td>
<td colspan="2">12</td>
<td colspan="2">14</td>
<td colspan="2">30</td>
<td colspan="2">38</td>
<td colspan="2">32</td>
<td colspan="2">126</td>
</tr>
<tr class="even">
<td></td>
<td>Number of Responders (%)</td>
<td>1</td>
<td>(7.7)</td>
<td>1</td>
<td>(8.3)</td>
<td>6</td>
<td>(42.9)</td>
<td>6</td>
<td>(20.0)</td>
<td>9</td>
<td>(23.7)</td>
<td>10</td>
<td>(31.3)</td>
<td>32</td>
<td>(25.4)</td>
</tr>
<tr class="odd">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">1.09</td>
<td colspan="2">9.00</td>
<td colspan="2">3.00</td>
<td colspan="2">3.72</td>
<td colspan="2">5.46</td>
<td colspan="2">4.09</td>
</tr>
<tr class="even">
<td></td>
<td>95% C.I. for Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">(0.01, 92.68)</td>
<td colspan="2">(0.78,447.61)</td>
<td colspan="2">(0.30, 149.31)</td>
<td colspan="2">(0.42, 176.62)</td>
<td colspan="2">(0.61, 256.10)</td>
<td colspan="2">(0.56, 180.00)</td>
</tr>
<tr class="odd">
<td></td>
<td>p-value</td>
<td></td>
<td></td>
<td colspan="2">1.000</td>
<td colspan="2">0.077</td>
<td colspan="2">0.412</td>
<td colspan="2">0.419</td>
<td colspan="2">0.136</td>
<td colspan="2">0.301</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">No ISR</td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>n</td>
<td colspan="2">35</td>
<td colspan="2">51</td>
<td colspan="2">32</td>
<td colspan="2">25</td>
<td colspan="2">21</td>
<td colspan="2">14</td>
<td colspan="2">143</td>
</tr>
<tr class="odd">
<td></td>
<td>Number of Responders (%)</td>
<td>6</td>
<td>(17.1)</td>
<td>7</td>
<td>(13.7)</td>
<td>8</td>
<td>(25.0)</td>
<td>6</td>
<td>(24.0)</td>
<td>9</td>
<td>(42.9)</td>
<td>6</td>
<td>(42.9)</td>
<td>36</td>
<td>(25.2)</td>
</tr>
<tr class="even">
<td></td>
<td>Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">0.77</td>
<td colspan="2">1.61</td>
<td colspan="2">1.53</td>
<td colspan="2">3.63</td>
<td colspan="2">3.63</td>
<td colspan="2">1.63</td>
</tr>
<tr class="odd">
<td></td>
<td>95% C.I. for Odds Ratio</td>
<td></td>
<td></td>
<td colspan="2">(0.24, 2.52)</td>
<td colspan="2">(0.49, 5.29)</td>
<td colspan="2">(0.43, 5.44)</td>
<td colspan="2">(1.06, 12.44)</td>
<td colspan="2">(0.73, 17.65)</td>
<td colspan="2">(0.63, 4.23)</td>
</tr>
<tr class="even">
<td></td>
<td>p-value</td>
<td></td>
<td></td>
<td colspan="2">0.664</td>
<td colspan="2">0.429</td>
<td colspan="2">0.513</td>
<td colspan="2">0.035</td>
<td colspan="2">0.076</td>
<td colspan="2">0.316</td>
</tr>
<tr class="odd">
<td colspan="16">N = Number of patients participating in the 24-week
protocol</td>
</tr>
<tr class="even">
<td colspan="16">n = Number of evaluable patients</td>
</tr>
<tr class="odd">
<td colspan="16">Patients with non-evaluable ACR criteria are
non-responders</td>
</tr>
<tr class="even">
<td colspan="16">p-value and confidence intervals are exact if expected
cell frequencies are less than 5</td>
</tr>
<tr class="odd">
<td colspan="16"><p><em>Biostatistics: 02AUG1999</em></p>
<p><em>/stat/il1ra/i960180abr/analysis/final/statfiles/tables/acrsusnr_960180_anyisr_xtabs.rtf</em></p></td>
</tr>
</tbody>
</table>

Appendix 4-8. Summary of Changes From Baseline\
in Endpoints of Signs and Symptoms at Week 24 (Study 990145)

  ---------------- ---------- -------------- ------------------------------ --------- ---------- ---------- ------------
                                                                            Placebo              Anakinra   

                                                                            (N = 251)            (N = 250)  

                                                                                                            

  Tender/painful                                                                                            
  joint count (0 -                                                                                          
  68)                                                                                                       

                   n                                                        168                  183        

                   Adjusted                                                 -8.65                -12.00     
                   mean                                                                                     

                   SE                                                       0.90                 0.88       

                   p-value                                                                       0.006      

                                                                                                            

  Swollen joint                                                                                             
  count (0 - 66)                                                                                            

                   n                                                        168                  183        

                   Adjusted                                                 -6.45                -6.78      
                   mean                                                                                     

                   SE                                                       0.61                 0.59       

                   p-value                                                                       0.686      

                                                                                                            

  Physician\'s                                                                                              
  assessment of                                                                                             
  disease activity                                                                                          
  (0 - 100)                                                                                                 

                   n                                                        169                  181        

                   Adjusted                                                 -20.08               -25.16     
                   mean                                                                                     

                   SE                                                       1.49                 1.45       

                   p-value                                                                       0.012      

                                                                                                            

  Subject\'s                                                                                                
  assessment of                                                                                             
  disease activity                                                                                          
  (0 - 100)                                                                                                 

                   n                                                        169                  181        

                   Adjusted                                                 -8.92                -17.73     
                   mean                                                                                     

                   SE                                                       1.66                 1.60       

                   p-value                                                                       \< 0.001   

                                                                                                            

  Subject\'s                                                                                                
  assessment of                                                                                             
  pain activity                                                                                             
  (0 - 100)                                                                                                 

                   n                                                        169                  181        

                   Adjusted                                                 -11.71               -19.00     
                   mean                                                                                     

                   SE                                                       1.79                 1.73       

                   p-value                                                                       0.003      

                                                                                                            

  Health                                                                                                    
  assessment                                                                                                
  questionnaire                                                                                             
  (0 - 3)                                                                                                   

                   n                                                        169                  183        

                   Adjusted                                                 -0.18                -0.29      
                   mean                                                                                     

                   SE                                                       0.03                 0.03       

                   p-value                                                                       0.017      

                              (Continued)                                                                   

  N =                         Number of                                                                     
                              subjects who                                                                  
                              were                                                                          
                              randomized as                                                                 
                              of 18 May 2000                                                                
                              and who                                                                       
                              received                                                                      

                              at least 1                                                                    
                              dose of study                                                                 
                              drug                                                                          

  n = Number of                                                                                             
  subjects                                                                                                  
  included in                                                                                               
  analysis at week                                                                                          
  24                                                                                                        

  SE = Standard                                                                                             
  error of the                                                                                              
  adjusted mean                                                                                             

  The adjusted                                                                                              
  mean and SE are                                                                                           
  estimated based                                                                                           
  on a repeated                                                                                             
  measures mixed                                                                                            
  model                                                                                                     

                              adjusted for                                                                  
                              study week,                                                                   
                              treatment by                                                                  
                              study week                                                                    
                              interaction,                                                                  
                              center and                                                                    
                              baseline                                                                      

                              value.                                                                        

  p-value                                                                                                   
  corresponds to                                                                                            
  the comparison                                                                                            
  between anakinra                                                                                          
  and placebo.                                                                                              

  ^a^ Based on log                                                                                          
  transformed                                                                                               
  values                                                                                                    
  ---------------- ---------- -------------- ------------------------------ --------- ---------- ---------- ------------

**Appendix 4-8. Summary of Changes From Baseline\
in Endpoints of Signs and Symptoms at Week 24 (Study 990145)
(Continued)\
**

+---+---+---+-----------------------------+------+---------+----+-----------+
|   |   |   |                             | Pla  |         | An |           |
|   |   |   |                             | cebo |         | ak |           |
|   |   |   |                             |      |         | in |           |
|   |   |   |                             |      |         | ra |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   |   |   |                             | (N = |         | (N |           |
|   |   |   |                             | 251) |         | =  |           |
|   |   |   |                             |      |         | 25 |           |
|   |   |   |                             |      |         | 0) |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
| C |   |   |                             |      |         |    |           |
| - |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| c |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| v |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| p |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| o |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| ( |   |   |                             |      |         |    |           |
| m |   |   |                             |      |         |    |           |
| g |   |   |                             |      |         |    |           |
| / |   |   |                             |      |         |    |           |
| d |   |   |                             |      |         |    |           |
| L |   |   |                             |      |         |    |           |
| ) |   |   |                             |      |         |    |           |
| ^ |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| ^ |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | n |   |                             | 170  |         | 1  |           |
|   |   |   |                             |      |         | 84 |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | A |   |                             | -    |         | -  |           |
|   | d |   |                             | 0.10 |         | 0. |           |
|   | j |   |                             |      |         | 51 |           |
|   | u |   |                             |      |         |    |           |
|   | s |   |                             |      |         |    |           |
|   | t |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
|   | d |   |                             |      |         |    |           |
|   | m |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
|   | a |   |                             |      |         |    |           |
|   | n |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | S |   |                             | 0.04 |         | 0. |           |
|   | E |   |                             |      |         | 03 |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | p |   |                             |      |         | \< |           |
|   | - |   |                             |      |         | 0  |           |
|   | v |   |                             |      |         | .0 |           |
|   | a |   |                             |      |         | 01 |           |
|   | l |   |                             |      |         |    |           |
|   | u |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
| E |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| y |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| h |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| o |   |   |                             |      |         |    |           |
| c |   |   |                             |      |         |    |           |
| y |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| d |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| m |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| o |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| ( |   |   |                             |      |         |    |           |
| m |   |   |                             |      |         |    |           |
| m |   |   |                             |      |         |    |           |
| / |   |   |                             |      |         |    |           |
| h |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| ) |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | n |   |                             | 170  |         | 1  |           |
|   |   |   |                             |      |         | 82 |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | A |   |                             | -    |         | -1 |           |
|   | d |   |                             | 5.98 |         | 6. |           |
|   | j |   |                             |      |         | 19 |           |
|   | u |   |                             |      |         |    |           |
|   | s |   |                             |      |         |    |           |
|   | t |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
|   | d |   |                             |      |         |    |           |
|   | m |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
|   | a |   |                             |      |         |    |           |
|   | n |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | S |   |                             | 1.25 |         | 1. |           |
|   | E |   |                             |      |         | 22 |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | p |   |                             |      |         | \< |           |
|   | - |   |                             |      |         | 0  |           |
|   | v |   |                             |      |         | .0 |           |
|   | a |   |                             |      |         | 01 |           |
|   | l |   |                             |      |         |    |           |
|   | u |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
| D |   |   |                             |      |         |    |           |
| u |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| o |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| o |   |   |                             |      |         |    |           |
| f |   |   |                             |      |         |    |           |
| m |   |   |                             |      |         |    |           |
| o |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| g |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| f |   |   |                             |      |         |    |           |
| f |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
| ( |   |   |                             |      |         |    |           |
| m |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| / |   |   |                             |      |         |    |           |
| d |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| y |   |   |                             |      |         |    |           |
| ) |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | n |   |                             | 169  |         | 1  |           |
|   |   |   |                             |      |         | 83 |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | A |   |                             | -3   |         | -4 |           |
|   | d |   |                             | 5.66 |         | 8. |           |
|   | j |   |                             |      |         | 17 |           |
|   | u |   |                             |      |         |    |           |
|   | s |   |                             |      |         |    |           |
|   | t |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
|   | d |   |                             |      |         |    |           |
|   | m |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
|   | a |   |                             |      |         |    |           |
|   | n |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | S |   |                             | 5.81 |         | 5. |           |
|   | E |   |                             |      |         | 62 |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   | p |   |                             |      |         | 0  |           |
|   | - |   |                             |      |         | .1 |           |
|   | v |   |                             |      |         | 12 |           |
|   | a |   |                             |      |         |    |           |
|   | l |   |                             |      |         |    |           |
|   | u |   |                             |      |         |    |           |
|   | e |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
| N |   | N |                             |      |         |    |           |
| = |   | u |                             |      |         |    |           |
|   |   | m |                             |      |         |    |           |
|   |   | b |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | r |                             |      |         |    |           |
|   |   | o |                             |      |         |    |           |
|   |   | f |                             |      |         |    |           |
|   |   | s |                             |      |         |    |           |
|   |   | u |                             |      |         |    |           |
|   |   | b |                             |      |         |    |           |
|   |   | j |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | c |                             |      |         |    |           |
|   |   | t |                             |      |         |    |           |
|   |   | s |                             |      |         |    |           |
|   |   | w |                             |      |         |    |           |
|   |   | h |                             |      |         |    |           |
|   |   | o |                             |      |         |    |           |
|   |   | w |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | r |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | r |                             |      |         |    |           |
|   |   | a |                             |      |         |    |           |
|   |   | n |                             |      |         |    |           |
|   |   | d |                             |      |         |    |           |
|   |   | o |                             |      |         |    |           |
|   |   | m |                             |      |         |    |           |
|   |   | i |                             |      |         |    |           |
|   |   | z |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | d |                             |      |         |    |           |
|   |   | a |                             |      |         |    |           |
|   |   | s |                             |      |         |    |           |
|   |   | o |                             |      |         |    |           |
|   |   | f |                             |      |         |    |           |
|   |   | 1 |                             |      |         |    |           |
|   |   | 8 |                             |      |         |    |           |
|   |   | M |                             |      |         |    |           |
|   |   | a |                             |      |         |    |           |
|   |   | y |                             |      |         |    |           |
|   |   | 2 |                             |      |         |    |           |
|   |   | 0 |                             |      |         |    |           |
|   |   | 0 |                             |      |         |    |           |
|   |   | 0 |                             |      |         |    |           |
|   |   | a |                             |      |         |    |           |
|   |   | n |                             |      |         |    |           |
|   |   | d |                             |      |         |    |           |
|   |   | w |                             |      |         |    |           |
|   |   | h |                             |      |         |    |           |
|   |   | o |                             |      |         |    |           |
|   |   | r |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | c |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | i |                             |      |         |    |           |
|   |   | v |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | d |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
|   |   | a |                             |      |         |    |           |
|   |   | t |                             |      |         |    |           |
|   |   | l |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | a |                             |      |         |    |           |
|   |   | s |                             |      |         |    |           |
|   |   | t |                             |      |         |    |           |
|   |   | 1 |                             |      |         |    |           |
|   |   | d |                             |      |         |    |           |
|   |   | o |                             |      |         |    |           |
|   |   | s |                             |      |         |    |           |
|   |   | e |                             |      |         |    |           |
|   |   | o |                             |      |         |    |           |
|   |   | f |                             |      |         |    |           |
|   |   | s |                             |      |         |    |           |
|   |   | t |                             |      |         |    |           |
|   |   | u |                             |      |         |    |           |
|   |   | d |                             |      |         |    |           |
|   |   | y |                             |      |         |    |           |
|   |   | d |                             |      |         |    |           |
|   |   | r |                             |      |         |    |           |
|   |   | u |                             |      |         |    |           |
|   |   | g |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
| n |   |   |                             |      |         |    |           |
| = |   |   |                             |      |         |    |           |
| N |   |   |                             |      |         |    |           |
| u |   |   |                             |      |         |    |           |
| m |   |   |                             |      |         |    |           |
| b |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| r |   |   |                             |      |         |    |           |
| o |   |   |                             |      |         |    |           |
| f |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
| u |   |   |                             |      |         |    |           |
| b |   |   |                             |      |         |    |           |
| j |   |   |                             |      |         |    |           |
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| c |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
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| n |   |   |                             |      |         |    |           |
| c |   |   |                             |      |         |    |           |
| l |   |   |                             |      |         |    |           |
| u |   |   |                             |      |         |    |           |
| d |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| d |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| n |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| l |   |   |                             |      |         |    |           |
| y |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
| i |   |   |                             |      |         |    |           |
| s |   |   |                             |      |         |    |           |
| a |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
| w |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| e |   |   |                             |      |         |    |           |
| k |   |   |                             |      |         |    |           |
| 2 |   |   |                             |      |         |    |           |
| 4 |   |   |                             |      |         |    |           |
+---+---+---+-----------------------------+------+---------+----+-----------+
| S |   |   |                             |      |         |    |           |
| E |   |   |                             |      |         |    |           |
| = |   |   |                             |      |         |    |           |
| S |   |   |                             |      |         |    |           |
| t |   |   |                             |      |         |    |           |
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+---+---+---+-----------------------------+------+---------+----+-----------+

Appendix 4-9. Adverse Events: Randomized, Placebo-controlled Studies

As shown in Table 4-19 adverse events were slightly more common in
anakinra groups than in placebo. Adverse events such as ISRs and
infections are discussed in Section 4.5. Other adverse events are
discussed briefly below.

In the large Safety Study (990757), 14.4% and 11.7% of subjects reported
headache in the 100 mg anakinra and placebo groups, respectively.

-   14 subjects (1.3%) in the anakinra group had severe headaches
    compared to none in the placebo group. All were female and the
    average time on study drug to onset of the event was 40.5 days. The
    median duration was 2 days.

    -   6 of the 14 (42.9%) were considered to be related to study drug
        by the investigators and 7 (50.0%) required medication.

    -   None of 14 were considered serious and only 2 subjects was
        withdrawn from study due to the event.

    -   11 of 14 (78.6%) had a medical history of relevance:

        -   6 with headache or migraine, and 5 each with hypertension
            and visual disturbances, respectively.

-   3 cases of migraine were also reported (2 in anakinra and 1 in
    placebo). These also occurred in women, were not considered related
    to study drug and did not result in withdrawal from study. The 2
    anakinra subjects had a history of headache or migraine, and 1 also
    had a history of hypertension and blurred vision.

All other most frequently observed adverse events had a relatively
similar incidence among groups. The incidence of influenza-like symptoms
and abdominal pain is slightly higher in the \> 100 mg anakinra group
compared with placebo. In these two categories, the incidence in the 100
mg anakinra group was lower than the \> 100 mg group. In fact, in the
large Safety Study (990757), conducted at 100 mg anakinra dose, the
incidence of influenza-like symptoms was similar in the 100 mg anakinra
and placebo groups (6.5% vs. 6.4%). The same was true for abdominal pain
(5.6% anakinra compared with 5.7% placebo). Therefore, there does not
appear to be an association between anakinra use and these events at the
100 mg dose.

Appendix 4-10. Serious Adverse Events by Body System and Preferred Term
for Placebo-controlled Studies

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">ANY</td>
<td>49</td>
<td>(6.5)</td>
<td></td>
<td>51</td>
<td>(8.4)</td>
<td></td>
<td>97</td>
<td>(7.1)</td>
<td></td>
<td>24</td>
<td>(12.2)</td>
<td></td>
<td>172</td>
<td>(7.9)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">MUSCULO-SKELETAL</td>
<td>22</td>
<td>(2.9)</td>
<td></td>
<td>20</td>
<td>(3.3)</td>
<td></td>
<td>30</td>
<td>(2.2)</td>
<td></td>
<td>8</td>
<td>(4.1)</td>
<td></td>
<td>58</td>
<td>(2.7)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Arthritis Rheumatoid</td>
<td>12</td>
<td>(1.6)</td>
<td></td>
<td>10</td>
<td>(1.6)</td>
<td></td>
<td>10</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>21</td>
<td>(1.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Arthralgia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>6</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Fracture</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Muscle Weakness</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Tendon Disorder</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Bursitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Osteoarthritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Synovitis</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Arthropathy</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Herniated Disc</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Osteomyelitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Avascular Necrosis Femoral Head</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Bone Disorder</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Dislocation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Joint Swelling</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pain Back</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Pain Limb</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 1 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">MUSCULO-SKELETAL (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Pain Neck</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Joint Stiffness</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Myopathy</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Osteonecrosis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">GASTROINTESTINAL</td>
<td>4</td>
<td>(0.5)</td>
<td></td>
<td>12</td>
<td>(2.0)</td>
<td></td>
<td>22</td>
<td>(1.6)</td>
<td></td>
<td>4</td>
<td>(2.0)</td>
<td></td>
<td>38</td>
<td>(1.7)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Pain Abdominal</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>5</td>
<td>(0.8)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>9</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Abdominal Hernia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Hemorrhage GI</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Nausea</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Vomiting</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Appendicitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Duodenal Ulcer</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Esophagitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Gastric Ulcer Hemorrhagic</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Intestinal Obstruction</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Abdominal Adhesions</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Bleeding Gingival</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Constipation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 2 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">GASTROINTESTINAL (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Diarrhea</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Diverticulitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Diverticulosis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Duodenal Ulcer Perforated</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Duodenitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Esophageal Ulceration</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Gastric Ulcer</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Gastritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Gastroenteritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Hiccup</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Oral Neoplasm</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Peptic Ulcer</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Stomach Perforation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Ileus Paralytic</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Melena</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">RESPIRATORY</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>7</td>
<td>(1.1)</td>
<td></td>
<td>22</td>
<td>(1.6)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>30</td>
<td>(1.4)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pneumonia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>11</td>
<td>(0.5)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Dyspnea</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 3 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">RESPIRATORY (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Bronchitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Chronic Obstructive Pulmonary Disease</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Embolism Pulmonary</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Epistaxis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Interstitial Lung Disease</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pneumonia Bacterial</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Pulmonary Carcinoma</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pulmonary Fibrosis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Asthma</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Bronchopneumonia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Edema Pulmonary</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Hemorrhage Pulmonary</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Infection Respiratory Tract</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>LRI</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Nasal Septum Perforation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pleural Effusion</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Pneumothorax</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pulmonary Neoplasm</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Respiratory Depression</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 4 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">RESPIRATORY (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Respiratory Insufficiency</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>URI</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">BODY AS A WHOLE</td>
<td>6</td>
<td>(0.8)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>10</td>
<td>(0.7)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>15</td>
<td>(0.7)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Pain Chest</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Fall</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Malaise</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Access Hematoma</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Adenocarcinoma</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Edema Peripheral</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Incisional Complication</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Injury</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Metastatic Neoplasm</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pain Pelvic</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Syncope</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Abnormal Laboratory Findings</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Inflammation</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Mass</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Neoplasm Benign</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 5 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">REPRODUCTIVE (FEMALE)<sup>a</sup></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(0.3)</td>
<td></td>
<td>3</td>
<td>(2.1)</td>
<td></td>
<td>7</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Menorrhagia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Breast Neoplasm Malignant</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Endometriosis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Menstrual Disorder</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Pelvic Inflammation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Uterine Carcinoma</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Uterine Hemorrhage</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Uterine Fibroid</td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">MYO/ENDO/PERICARDIAL</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>7</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>9</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Angina Pectoris</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Coronary Artery Disorder</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Myocardial Infarction</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Pain Chest</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Aortic Stenosis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Heart Valve Disorders</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Pericarditis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Thrombosis Coronary</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">SKIN AND APPENDAGES</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>5</td>
<td>(0.4)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>9</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="17">Page 6 of 12</td>
</tr>
<tr class="odd">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="even">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="odd">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="even">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="odd">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="even">
<td colspan="17"></td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">SKIN AND APPENDAGES (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Cellulitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Basal Cell Carcinoma</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Cyst Unspecified</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Melanoma Malignant</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Urticaria</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Wound</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Wound Dehiscence</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Lesion Skin</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">CNS/PNS</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>6</td>
<td>(0.4)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>8</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Cerebrovascular Disorder</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Dizziness</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Gait Abnormal</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Hemiparesis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Hemorrhage Subarachnoid</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Hypoesthesia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">HEMATOLOGIC</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>8</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Anemia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 7 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">HEMATOLOGIC (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Granulocytopenia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Leukopenia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Thrombocytopenia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Hematoma</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Hodgkin's Disease</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">RESISTANCE MECHANISM</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>5</td>
<td>(0.4)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>8</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Infection</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Abscess</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Empyema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Herpes Zoster</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Infection Bacterial</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">CARDIOVASCULAR</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>7</td>
<td>(0.5)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>7</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Cardiac Failure</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Hypertension</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Hypotension</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">VASCULAR DISORDERS</td>
<td>6</td>
<td>(0.8)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>7</td>
<td>(0.5)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>7</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 8 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">VASCULAR DISORDERS (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Thrombosis Venous Deep</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Ischemia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Peripheral Ischemia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Thrombosis Venous</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Transient Ischemic Attack</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Vascular Disorder</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Aneurysm</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Arteritis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Gangrene</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Thromboembolism</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">HEART RATE/RHYTHM</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.4)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>6</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Arrhythmia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Fibrillation Atrial</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Bundle Branch Block</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Tachycardia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">NOT CODED</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>5</td>
<td>(0.8)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Hosp for Surgery Rt Hand (Neurolysis, Synovectomie)</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 9 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">NOT CODED (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Left Ankle Replacement- Indication Unreported</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Scheduled Hip Replacement Indication Unreported</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Scheduled Hospitalization for Ia Injection</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Withdrawal of Consent, Hospitalisation for Reintroduction</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Hospitalisation- Indication Unreported</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">PSYCHIATRIC DISORDER</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Depression</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Anxiety</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Drug Dependence</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Suicide Accomplished</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">METABOLIC/NUTRITION</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Dehydration</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Acidosis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Hyponatremia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">URINARY DISORDERS</td>
<td>4</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Renal Failure</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 10 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">URINARY DISORDERS (Cont'd)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<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></td>
<td>Pyelonephritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>UTI</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Bladder Carcinoma</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Renal Calculus</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">APPLICATION SITE</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>ISR - Inflammation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>ISR - Erythema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>ISR - Pain</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>ISR - Pruritus</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>ISR - Urticaria</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">LIVER AND BILIARY</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Cholelithiasis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Hepatic Neoplasm Benign</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Cholecystitis</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">DEVICE COMPLICATION</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Device Complication</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 11 of 12</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-10.** **Serious Adverse Events by Body System and Preferred
Term for Placebo-controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td colspan="2">BODY SYSTEM</td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td></td>
<td>Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">ENDOCRINE DISORDERS</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Thyroid Neoplasm Malignant</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">REPRODUCTIVE (MALE)<sup>a</sup></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Prostate Carcinoma</td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="17">Page 12 of 12</td>
</tr>
<tr class="odd">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="even">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="odd">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="even">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="odd">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="even">
<td colspan="17"></td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_ser_bcpterm.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

Appendix 4-11. Death Narratives

#######  {#section-1 .FlushLeftBold .unnumbered}

####### Monotherapy Study (0560) {#monotherapy-study-0560-2 .FlushLeftBold .unnumbered}

No on-study deaths were reported. Two deaths were reported ≥ 3 months
and 1 death was reported \< 30 days after study drug was discontinued.
Only 1 death was reported by the investigator as related to anakinra:

-   A 55-year-old man with a history of smoking who received 30 mg
    anakinra daily in the Monotherapy Study (0560), was diagnosed with
    small cell lung cancer approximately 3 weeks after completing the
    study. The subject died approximately 7 weeks later. The small cell
    lung cancer was considered by the investigator to be possibly
    related to study drug.

####### Low Dose Monotherapy Study (960182) {#low-dose-monotherapy-study-960182-1 .FlushLeftBold .unnumbered}

No deaths were reported in this study.

####### MTX Combination Study (960180) {#mtx-combination-study-960180-2 .FlushLeftBold .unnumbered}

No deaths were reported.

####### Confirmatory Efficacy Study (990145) {#confirmatory-efficacy-study-990145-2 .FlushLeftBold .unnumbered}

One death was reported \> 30 days after study drug discontinuation among
the 501 subjects who were included in the 24-week analysis of signs and
symptoms data:

-   One subject died 37 days after discontinuing study drug (treatment
    assignment remains blinded) from an event that started during the
    study period. The investigator considered the event unrelated to
    study drug. The subject, an 80-year-old man with a history of
    chronic interstitial lung disease, was hospitalized approximately
    2 months after start of study drug for congestive heart failure
    (CHF) deemed by the investigator to be related to the interstitial
    pulmonary disease. The subject was discharged from the hospital 2
    days later and withdrawn from study drug. The subject's respiratory
    status deteriorated, and he was re-hospitalized approximately 2
    weeks later. During hospitalization, the subject developed atrial
    fibrillation, failed to respond to treatment and chose to be
    discharged home. He died 11 days later.

####### Safety Study (990757) {#safety-study-990757-1 .FlushLeftBold .unnumbered}

The 5 deaths (0.4%) reported among the 1399 treated subjects during the
24-week blinded study period are discussed below:

-   The first subject (100 mg anakinra daily), a 60-year-old woman with
    a history of interstitial lung disease and diabetes, was
    hospitalized for respiratory distress after approximately 4.5 months
    on study. A chest radiograph revealed bilateral infiltrates.
    Anakinra was discontinued and treatment consisted of nasal oxygen,
    intravenous Solu-Cortef, piperacillin/tazobactam, and Bactrim. An
    opportunistic infection was suspected but never confirmed. The
    subject's condition continued to deteriorate and she died after
    approximately 5 months on study. An autopsy revealed bilateral
    advanced chronic lung disease with honeycomb lung parenchyma and
    possible thromboemboli. The investigator thought there was a
    reasonable possibility that the event was related to study drug.

-   The second subject (100 mg anakinra daily) committed suicide after
    56 days on study drug. This subject had a psychiatric history that
    included panic attacks and depression dating from 1980 and
    continuing at the time of study entry.

-   The third subject (100 mg anakinra daily) was diagnosed with
    metastatic melanoma 105 days after beginning blinded study drug. The
    admission documents at the time of the subject's diagnosis mentioned
    a history of melanoma, but no date was given (the protocol specified
    that a history of cancer within 5 years is exclusionary). The
    subject subsequently died at home.

-   The fourth subject (placebo) died of a myocardial infarction 53 days
    after beginning blinded study drug. The subject had a medical
    history of diabetes and hypertension.

-   The fifth subject (100 mg anakinra daily) died of an upper GI
    hemorrhage after approximately 1 month on study drug. This subject
    had a medical history that included esophagitis, gastric ulcers, and
    gastritis. This patient died within 30 days post study.

####### Monotherapy Extension Study (0564) {#monotherapy-extension-study-0564 .FlushLeftBold .unnumbered}

Two subjects died in study 0564E1. One was considered related to
anakinra therapy:

-   A 72-year-old woman, who was hospitalized with endocarditis after
    776 days of treatment with anakinra 30 mg daily. At the time of
    diagnosis, her white blood cell (WBC) count was 41.7 x 10^9^/L, CRP
    was 34.5 mg/dL, and temperature was 39°C. An echocardiogram revealed
    changes suspicious for endocarditis. Foot ulcerations were thought
    to be the source of the endocarditis. Despite treatment with IV
    penicillin and gentamicin, and later imipenem, her condition
    deteriorated. She died of pulmonary edema and circulatory failure 3
    weeks later.

####### MTX Combination Extension Study (960181) {#mtx-combination-extension-study-960181 .FlushLeftBold .unnumbered}

In study 960181, 5 subjects died. One was considered related to anakinra
therapy:

This case involved a 70-year old man receiving 2.0 mg/kg who had sepsis.
He received long-term methotrexate and corticosteroid treatment and was
initially hospitalized with buttock cellulitis and an ischio-rectal
abscess (considered unrelated to study drug). Methotrexate and anakinra
treatment were withheld. He was treated with surgical drainage and IV
antibiotics and initially recovered, but relapsed after groin trauma. He
was hospitalized with retroperitoneal and abdominal wall abscesses. His
condition subsequently deteriorated and he died 818 days after starting
study drug.

Appendix 4-12. Subject Incidence of Treatment-Emergent AEs Leading to
Withdrawal for Placebo-Controlled Studies

  --------------------------------------------------------------------------- -------------------- --------- -------- -- ---------- ------- -- ------- -------- -- ------ -------- -- ------- -------- --
                                                                                                                         Anakinra                                                                      
                                                                                                                         (mg)                                                                          

                                                                                                   Placebo               \< 100                100                 \> 100             All              

  Preferred Term - n (%)                                                                           (N = 759)             (N = 610)             (N =                (N =               (N =             
                                                                                                                                               1367)               196)               2173)            

                                                                                                                                                                                                       

  Any                                                                                              88        (11.6)      58         (9.5)      186     (13.6)      36     (18.4)      280     (12.9)   

                                                                                                                                                                                                       

  Injection Site Reaction                                                                          10        (1.3)       8          (1.3)      100     (7.3)       14     (7.1)       122     (5.6)    

  Arthritis Rheumatoid                                                                             46        (6.1)       28         (4.6)      22      (1.6)       7      (3.6)       57      (2.6)    

  Headache                                                                                         4         (0.5)       0          (0.0)      8       (0.6)       0      (0.0)       8       (0.4)    

  Pain Abdominal                                                                                   3         (0.4)       1          (0.2)      7       (0.5)       0      (0.0)       8       (0.4)    

  Arthralgia                                                                                       1         (0.1)       1          (0.2)      3       (0.2)       2      (1.0)       6       (0.3)    

  Fatigue                                                                                          1         (0.1)       0          (0.0)      5       (0.4)       1      (0.5)       6       (0.3)    

  Leukopenia                                                                                       0         (0.0)       4          (0.7)      1       (0.1)       1      (0.5)       6       (0.3)    

  Dizziness                                                                                        0         (0.0)       0          (0.0)      5       (0.4)       0      (0.0)       5       (0.2)    

  Dyspnea                                                                                          1         (0.1)       1          (0.2)      4       (0.3)       0      (0.0)       5       (0.2)    

  Pneumonia                                                                                        0         (0.0)       2          (0.3)      3       (0.2)       0      (0.0)       5       (0.2)    

  Granulocytopenia                                                                                 0         (0.0)       1          (0.2)      0       (0.0)       3      (1.5)       4       (0.2)    

  Nausea                                                                                           0         (0.0)       0          (0.0)      4       (0.3)       0      (0.0)       4       (0.2)    

  Arthritis                                                                                        1         (0.1)       1          (0.2)      2       (0.1)       0      (0.0)       3       (0.1)    

  Chronic Obstructive Pulmonary Disease                                                            0         (0.0)       2          (0.3)      1       (0.1)       0      (0.0)       3       (0.1)    

  Pain Limb                                                                                        1         (0.1)       2          (0.3)      1       (0.1)       0      (0.0)       3       (0.1)    

  Palpitation                                                                                      1         (0.1)       1          (0.2)      2       (0.1)       0      (0.0)       3       (0.1)    

  Pruritus                                                                                         1         (0.1)       1          (0.2)      2       (0.1)       0      (0.0)       3       (0.1)    

  Rash                                                                                             1         (0.1)       1          (0.2)      2       (0.1)       0      (0.0)       3       (0.1)    

  Alopecia                                                                                         0         (0.0)       0          (0.0)      2       (0.1)       0      (0.0)       2       (0.1)    

  Constipation                                                                                     0         (0.0)       0          (0.0)      2       (0.1)       0      (0.0)       2       (0.1)    

  Depression                                                                                       0         (0.0)       1          (0.2)      1       (0.1)       0      (0.0)       2       (0.1)    

  Diarrhea                                                                                         2         (0.3)       0          (0.0)      2       (0.1)       0      (0.0)       2       (0.1)    

  Page 1 of 6                                                                                                                                                                                          

  Includes studies 0560, 960180, 960182, 990145, and 990757                                                                                                                                            

  Injection Site Reaction includes all perferred terms under the Application                                                                                                                           
  Site body system.                                                                                                                                                                                    

  N = Number of randomized subjects who received at least 1 dose of study                                                                                                                              
  drug                                                                                                                                                                                                 

  n = Number of subjects reporting at least 1 occurrence of an adverse event                                                                                                                           

  \% = (n/N) x 100                                                                                                                                                                                     

  ^a^ Reproductive AE rates are gender-specific.                                                                                                                                                       

  /stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_isrpterm.sas                                                                                                                            
  Output: t_ae_isrpterm_wdraw.rtf (generated 15JUN2001)                                                                                                                                                
  --------------------------------------------------------------------------- -------------------- --------- -------- -- ---------- ------- -- ------- -------- -- ------ -------- -- ------- -------- --

**Appendix 4-12. Subject Incidence of Treatment-Emergent AEs Leading to
Withdrawal for Placebo-Controlled Studies**

  --------------------------------------------------------------------------- -------------------- --------- ------- -- ---------- ------- -- ------- ------- -- ------ ------- -- ------- ------- --
                                                                                                                        Anakinra                                                                   
                                                                                                                        (mg)                                                                       

                                                                                                   Placebo              \< 100                100                \> 100            All             

  Preferred Term - n (%)                                                                           (N = 759)            (N = 610)             (N =               (N =              (N =            
                                                                                                                                              1367)              196)              2173)           

                                                                                                                                                                                                   

  Edema Periorbital                                                                                0         (0.0)      0          (0.0)      2       (0.1)      0      (0.0)      2       (0.1)   

  Edema Peripheral                                                                                 0         (0.0)      1          (0.2)      1       (0.1)      0      (0.0)      2       (0.1)   

  Eosinophilia                                                                                     0         (0.0)      0          (0.0)      1       (0.1)      1      (0.5)      2       (0.1)   

  Infection                                                                                        0         (0.0)      0          (0.0)      1       (0.1)      1      (0.5)      2       (0.1)   

  Interstitial Lung Disease                                                                        0         (0.0)      0          (0.0)      2       (0.1)      0      (0.0)      2       (0.1)   

  Muscle Weakness                                                                                  0         (0.0)      0          (0.0)      2       (0.1)      0      (0.0)      2       (0.1)   

  Pain Chest Cardiac                                                                               0         (0.0)      1          (0.2)      0       (0.0)      1      (0.5)      2       (0.1)   

  Pneumonia Bacterial                                                                              0         (0.0)      0          (0.0)      2       (0.1)      0      (0.0)      2       (0.1)   

  Pulmonary Carcinoma                                                                              2         (0.3)      1          (0.2)      1       (0.1)      0      (0.0)      2       (0.1)   

  Pulmonary Fibrosis                                                                               0         (0.0)      0          (0.0)      2       (0.1)      0      (0.0)      2       (0.1)   

  Rhinitis                                                                                         0         (0.0)      0          (0.0)      2       (0.1)      0      (0.0)      2       (0.1)   

  Thrombocytopenia                                                                                 0         (0.0)      0          (0.0)      2       (0.1)      0      (0.0)      2       (0.1)   

  UTI                                                                                              0         (0.0)      0          (0.0)      1       (0.1)      1      (0.5)      2       (0.1)   

  Urticaria                                                                                        0         (0.0)      1          (0.2)      1       (0.1)      0      (0.0)      2       (0.1)   

  Breast Neoplasm Malignant^a^                                                                     0         (0.0)      0          (0.0)      0       (0.0)      1      (0.7)      1       (0.1)   

  Menorrhagia^a^                                                                                   0         (0.0)      0          (0.0)      1       (0.1)      0      (0.0)      1       (0.1)   

  Abdomen Enlarged                                                                                 0         (0.0)      0          (0.0)      1       (0.1)      0      (0.0)      1       (0.0)   

  Abscess Oral                                                                                     0         (0.0)      0          (0.0)      1       (0.1)      0      (0.0)      1       (0.0)   

  Acidosis                                                                                         0         (0.0)      0          (0.0)      1       (0.1)      0      (0.0)      1       (0.0)   

  Adenocarcinoma                                                                                   0         (0.0)      0          (0.0)      1       (0.1)      0      (0.0)      1       (0.0)   

  Albuminuria                                                                                      0         (0.0)      1          (0.2)      0       (0.0)      0      (0.0)      1       (0.0)   

  Allergic Rash                                                                                    0         (0.0)      1          (0.2)      0       (0.0)      0      (0.0)      1       (0.0)   

  Allergic Reaction                                                                                0         (0.0)      1          (0.2)      0       (0.0)      0      (0.0)      1       (0.0)   

  Anemia                                                                                           1         (0.1)      0          (0.0)      1       (0.1)      0      (0.0)      1       (0.0)   

  Page 2 of 6                                                                                                                                                                                      

  Includes studies 0560, 960180, 960182, 990145, and 990757                                                                                                                                        

  Injection Site Reaction includes all perferred terms under the Application                                                                                                                       
  Site body system.                                                                                                                                                                                

  N = Number of randomized subjects who received at least 1 dose of study                                                                                                                          
  drug                                                                                                                                                                                             

  n = Number of subjects reporting at least 1 occurrence of an adverse event                                                                                                                       

  \% = (n/N) x 100                                                                                                                                                                                 

  ^a^ Reproductive AE rates are gender-specific.                                                                                                                                                   

  /stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_isrpterm.sas                                                                                                                        
  Output: t_ae_isrpterm_wdraw.rtf (generated 15JUN2001)                                                                                                                                            
  --------------------------------------------------------------------------- -------------------- --------- ------- -- ---------- ------- -- ------- ------- -- ------ ------- -- ------- ------- --

**Appendix 4-12. Subject Incidence of Treatment-Emergent AEs Leading to
Withdrawal for Placebo-Controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Anxiety</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Aortic Stenosis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Appendicitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Asthma</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Bleeding Gingival</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Bronchitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Bursitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cellulitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Cough</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cough Dry</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Edema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Edema Tongue</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Embolism Pulmonary</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Epistaxis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Erythema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Fall</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Fever</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Fibrillation Atrial</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Fracture</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gastroenteritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hematoma</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hemiparesis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hemorrhage Pulmonary</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hemorrhage Subarachnoid</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 3 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">Injection Site Reaction includes all perferred terms
under the Application Site body system.</td>
</tr>
<tr class="even">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="odd">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="even">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="odd">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_isrpterm.sas</p>
<p>Output: t_ae_isrpterm_wdraw.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-12. Subject Incidence of Treatment-Emergent AEs Leading to
Withdrawal for Placebo-Controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hepatitis Infectious</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hypoesthesia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hypotension</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Joint Stiffness</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Keratitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">LRI</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Lymphadenopathy</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Malaise</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Melanoma Malignant</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Metastatic Neoplasm</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Migraine</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Musculo-Skeletal Disorder</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Nervousness</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Osteomyelitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pain</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pain Back</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pain Chest Non-Cardiac</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pain Rectal</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pneumonia Viral</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pruritic Erythema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Rash Maculo-Papular</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Renal Failure</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Rigors</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Sinusitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 4 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">Injection Site Reaction includes all perferred terms
under the Application Site body system.</td>
</tr>
<tr class="even">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="odd">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="even">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="odd">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_isrpterm.sas</p>
<p>Output: t_ae_isrpterm_wdraw.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-12. Subject Incidence of Treatment-Emergent AEs Leading to
Withdrawal for Placebo-Controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Skin Nodule</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Somnolence</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Stomach Perforation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Stomatitis Ulcerative</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Suicide Accomplished</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Sweating Increased</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Synovitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Tachycardia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Thyroid Neoplasm Malignant</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Tinnitus</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Transient Ischemic Attack</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">URI</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Wheezing</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Abnormal Laboratory Findings</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Arrhythmia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Arteritis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Asthenia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cerebrovascular Disorder</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Dermatitis Fungal</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Duodenal Ulcer</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Flatulence</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Flushing</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Gait Abnormal</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gangrene</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 5 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">Injection Site Reaction includes all perferred terms
under the Application Site body system.</td>
</tr>
<tr class="even">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="odd">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="even">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="odd">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="even">
<td colspan="17"></td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_isrpterm.sas</p>
<p>Output: t_ae_isrpterm_wdraw.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-12. Subject Incidence of Treatment-Emergent AEs Leading to
Withdrawal for Placebo-Controlled Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hallucination</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hematochezia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hemorrhage Vaginal<sup>a</sup></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hepatic Function Abnormal</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Herpes Zoster</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hodgkin's Disease</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hypertonia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Infection Respiratory Tract</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Inflammation</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Joint Swelling</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Lesion Genital Male<sup>a</sup></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Melena</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Muscle Contractions Involuntary</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Myalgia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Myocardial Infarction</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Myopathy</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Prostate Carcinoma<sup>a</sup></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pulse Weak</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Sore Throat</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Syncope</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Thromboembolism</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="17">Page 6 of 6</td>
</tr>
<tr class="odd">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="even">
<td colspan="17">Injection Site Reaction includes all perferred terms
under the Application Site body system.</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td colspan="17"></td>
</tr>
<tr class="even">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_isrpterm.sas</p>
<p>Output: t_ae_isrpterm_wdraw.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

Appendix 4-13. Infections by Preferred Term for Placebo-controlled
Studies

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Any</td>
<td>275</td>
<td>(36.2)</td>
<td></td>
<td>227</td>
<td>(37.2)</td>
<td></td>
<td>544</td>
<td>(39.8)</td>
<td></td>
<td>84</td>
<td>(42.9)</td>
<td></td>
<td>855</td>
<td>(39.3)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">URI</td>
<td>95</td>
<td>(12.5)</td>
<td></td>
<td>63</td>
<td>(10.3)</td>
<td></td>
<td>174</td>
<td>(12.7)</td>
<td></td>
<td>23</td>
<td>(11.7)</td>
<td></td>
<td>260</td>
<td>(12.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Sinusitis</td>
<td>36</td>
<td>(4.7)</td>
<td></td>
<td>25</td>
<td>(4.1)</td>
<td></td>
<td>86</td>
<td>(6.3)</td>
<td></td>
<td>8</td>
<td>(4.1)</td>
<td></td>
<td>119</td>
<td>(5.5)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Flu-Like Symptoms</td>
<td>35</td>
<td>(4.6)</td>
<td></td>
<td>29</td>
<td>(4.8)</td>
<td></td>
<td>74</td>
<td>(5.4)</td>
<td></td>
<td>14</td>
<td>(7.1)</td>
<td></td>
<td>117</td>
<td>(5.4)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">UTI</td>
<td>37</td>
<td>(4.9)</td>
<td></td>
<td>23</td>
<td>(3.8)</td>
<td></td>
<td>62</td>
<td>(4.5)</td>
<td></td>
<td>10</td>
<td>(5.1)</td>
<td></td>
<td>95</td>
<td>(4.4)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Bronchitis</td>
<td>26</td>
<td>(3.4)</td>
<td></td>
<td>18</td>
<td>(3.0)</td>
<td></td>
<td>48</td>
<td>(3.5)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>69</td>
<td>(3.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Infection</td>
<td>15</td>
<td>(2.0)</td>
<td></td>
<td>8</td>
<td>(1.3)</td>
<td></td>
<td>38</td>
<td>(2.8)</td>
<td></td>
<td>6</td>
<td>(3.1)</td>
<td></td>
<td>52</td>
<td>(2.4)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Fever</td>
<td>11</td>
<td>(1.4)</td>
<td></td>
<td>13</td>
<td>(2.1)</td>
<td></td>
<td>15</td>
<td>(1.1)</td>
<td></td>
<td>12</td>
<td>(6.1)</td>
<td></td>
<td>40</td>
<td>(1.8)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Moniliasis Genital<sup>a</sup></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>8</td>
<td>(1.7)</td>
<td></td>
<td>14</td>
<td>(1.4)</td>
<td></td>
<td>1</td>
<td>(0.7)</td>
<td></td>
<td>23</td>
<td>(1.4)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Herpes Simplex</td>
<td>9</td>
<td>(1.2)</td>
<td></td>
<td>10</td>
<td>(1.6)</td>
<td></td>
<td>14</td>
<td>(1.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>25</td>
<td>(1.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Conjunctivitis</td>
<td>10</td>
<td>(1.3)</td>
<td></td>
<td>8</td>
<td>(1.3)</td>
<td></td>
<td>11</td>
<td>(0.8)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>22</td>
<td>(1.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">LRI</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>6</td>
<td>(1.0)</td>
<td></td>
<td>12</td>
<td>(0.9)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>20</td>
<td>(0.9)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pharyngitis</td>
<td>7</td>
<td>(0.9)</td>
<td></td>
<td>10</td>
<td>(1.6)</td>
<td></td>
<td>6</td>
<td>(0.4)</td>
<td></td>
<td>4</td>
<td>(2.0)</td>
<td></td>
<td>20</td>
<td>(0.9)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Infection Fungal</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>13</td>
<td>(1.0)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>18</td>
<td>(0.8)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pneumonia</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>4</td>
<td>(0.7)</td>
<td></td>
<td>14</td>
<td>(1.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>18</td>
<td>(0.8)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Cough</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>17</td>
<td>(1.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>17</td>
<td>(0.8)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Abscess Oral</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>10</td>
<td>(0.7)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>16</td>
<td>(0.7)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Bursitis</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>8</td>
<td>(1.3)</td>
<td></td>
<td>5</td>
<td>(0.4)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>16</td>
<td>(0.7)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gastroenteritis Viral</td>
<td>4</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.7)</td>
<td></td>
<td>11</td>
<td>(0.8)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>15</td>
<td>(0.7)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Sore Throat</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>15</td>
<td>(1.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>15</td>
<td>(0.7)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gastroenteritis</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>10</td>
<td>(0.7)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>14</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Infection Bacterial</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>14</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Dermatitis Fungal</td>
<td>8</td>
<td>(1.1)</td>
<td></td>
<td>6</td>
<td>(1.0)</td>
<td></td>
<td>5</td>
<td>(0.4)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>13</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 1 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_infect.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-13. Infections by Preferred Term for Placebo-controlled
Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Herpes Zoster</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>11</td>
<td>(0.8)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>13</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Otitis Media</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>5</td>
<td>(0.8)</td>
<td></td>
<td>7</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>13</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Stomatitis Ulcerative</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>11</td>
<td>(1.8)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>13</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cellulitis</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>12</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Infection Viral</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>12</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Rigors</td>
<td>6</td>
<td>(0.8)</td>
<td></td>
<td>7</td>
<td>(1.1)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>12</td>
<td>(0.6)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Otitis</td>
<td>6</td>
<td>(0.8)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>11</td>
<td>(0.5)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Upper Respiratory Tract Congestion</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>11</td>
<td>(0.8)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>11</td>
<td>(0.5)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Cystitis</td>
<td>8</td>
<td>(1.1)</td>
<td></td>
<td>4</td>
<td>(0.7)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(1.5)</td>
<td></td>
<td>10</td>
<td>(0.5)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Laryngitis</td>
<td>4</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.7)</td>
<td></td>
<td>6</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>10</td>
<td>(0.5)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Diarrhea</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>9</td>
<td>(0.7)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>9</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Paronychia</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>6</td>
<td>(0.4)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>9</td>
<td>(0.4)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pharyngitis Bacterial</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>7</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Stomatitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(1.0)</td>
<td></td>
<td>7</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Abscess</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>6</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Infection Respiratory Tract</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>6</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Moniliasis Oral</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>6</td>
<td>(0.3)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Vaginitis<sup>a</sup></td>
<td>4</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>3</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Dysuria</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>4</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Furunculosis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pustule</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Respiratory Tract Congestion</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Vomiting</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>5</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Acne</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 2 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_infect.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-13. Infections by Preferred Term for Placebo-controlled
Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Nausea</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.3)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pyuria</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">URI - Viral</td>
<td>5</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>4</td>
<td>(0.2)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Folliculitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Osteomyelitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pleurisy</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Rhinitis</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Skin Ulceration</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Wound</td>
<td>4</td>
<td>(0.5)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>3</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cough Productive</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Dermatitis</td>
<td>2</td>
<td>(0.3)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gingivitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Keratitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Lymphadenopathy</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Moniliasis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Nail Disorder</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pneumonia Bacterial</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Sialoadenitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Skin Nodule</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>2</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Leukorrhea<sup>a</sup></td>
<td>3</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pelvic Inflammation<sup>a</sup></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.7)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Vaginitis Bacterial<sup>a</sup></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Appendicitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Asthma</td>
<td>3</td>
<td>(0.4)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 3 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_infect.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-13. Infections by Preferred Term for Placebo-controlled
Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Blepharitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Blisters</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Bronchiectasis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Bronchitis Viral</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Bronchopneumonia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Colitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Conjunctivitis Bacterial</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cough Dry</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Cyst Unspecified</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Dehydration</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Diverticulitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Dyspnea</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Empyema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Erysipelas</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Esophageal Ulceration</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Esophagitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Esophagitis Fungal</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Fatigue</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Gastritis Bacterial</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Glossitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Headache</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hemorrhoids</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Hepatitis Infectious</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">ISR - Infection</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 4 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_infect.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-13. Infections by Preferred Term for Placebo-controlled
Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">ISR - Not Specified</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">ISR - Urticaria</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Incisional Erythema</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Infection Respiratory Tract Viral</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Inflammation</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Iritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Keratoconjunctivitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pain</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Parasitemia</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Parasitism</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pleural Effusion</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pneumonia Viral</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pruritus Genital</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Pulmonary Infiltration</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Pyelonephritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Rash Maculo-Papular</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Tendinitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Tooth Disorder</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Tracheitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.5)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Urethritis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Vasculitis</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Verruca</td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>1</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Allergic Reaction</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Allergic Rhinitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="17">Page 5 of 6</td>
</tr>
<tr class="even">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="odd">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="even">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="odd">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="even">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_infect.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

**Appendix 4-13. Infections by Preferred Term for Placebo-controlled
Studies**

<table>
<colgroup>
<col style="width: 1%" />
<col style="width: 29%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="12">Anakinra (mg)</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="3">Placebo</td>
<td colspan="3">&lt; 100</td>
<td colspan="3">100</td>
<td colspan="3">&gt; 100</td>
<td colspan="3">All</td>
</tr>
<tr class="odd">
<td colspan="2">Preferred Term - n (%)</td>
<td colspan="3">(N = 759)</td>
<td colspan="3">(N = 610)</td>
<td colspan="3">(N = 1367)</td>
<td colspan="3">(N = 196)</td>
<td colspan="3">(N = 2173)</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>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Arthritis Rheumatoid</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Cholecystitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Dermatitis Contact</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Gangrene</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Gastritis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Hematoma</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Leukoplakia Oral</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Rash</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Scleritis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Sinusitis Viral</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Tooth Caries</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Uveitis</td>
<td>1</td>
<td>(0.1)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Vaginitis Fungal<sup>a</sup></td>
<td>1</td>
<td>(0.2)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
<td>0</td>
<td>(0.0)</td>
<td></td>
</tr>
<tr class="even">
<td colspan="17">Page 6 of 6</td>
</tr>
<tr class="odd">
<td colspan="17">Includes studies 0560, 960180, 960182, 990145, and
990757</td>
</tr>
<tr class="even">
<td colspan="17">N = Number of randomized subjects who received at least
1 dose of study drug</td>
</tr>
<tr class="odd">
<td colspan="17">n = Number of subjects reporting at least 1 occurrence
of an adverse event</td>
</tr>
<tr class="even">
<td colspan="17">% = (n/N) x 100</td>
</tr>
<tr class="odd">
<td colspan="17"><sup>a</sup> Reproductive AE rates are
gender-specific.</td>
</tr>
<tr class="even">
<td colspan="17"></td>
</tr>
<tr class="odd">
<td
colspan="17"><p>/stat/il1ra/fda_brfpkg/analysis/safety/statfiles/tables/t_ae_pterm.sas</p>
<p>Output: t_ae_pterm_infect.rtf (generated 15JUN2001)</p></td>
</tr>
</tbody>
</table>

Appendix 4-14. WHO Toxicity grading criteria for hematology and
biochemistry variables

+---------------------+-------+-----+--------+--------+--------+-----+
|                     | DIRE  |     |        |        |        |     |
|                     | CTION |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| VARIABLE            | OF    | GR  | GRADE  | GRADE  | GRADE  | GR  |
|                     | C     | ADE | 1      | 2      | 3      | ADE |
|                     | HANGE | O   |        |        |        | 4   |
+---------------------+-------+-----+--------+--------+--------+-----+
| HEMATOLOGY          |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Hemoglobin (g/L)    | Dec   | [\> | \<LL - | \<     | \      | \<  |
|                     | rease | ]{. | 0      | 0.80-0 | <0.65- | 0.5 |
|                     |       | und | .80xLL | .65xLL | 0.5xLL | xLL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }LL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Hematocrit (%)      | Dec   | [\> | \<LL - | \<     | \      | \<  |
|                     | rease | ]{. | 0      | 0.80-0 | <0.65- | 0.5 |
|                     |       | und | .80xLL | .65xLL | 0.5xLL | xLL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }LL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Total White Cell    | Dec   | [\> | \<LL - | \      | \      | \<0 |
| Count (x10^9^/L)    | rease | ]{. | 0      | <0.75- | <0.5-0 | .25 |
|                     |       | und | .75xLL | 0.5xLL | .25xLL | xLL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }LL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Total Neutrophils   | Dec   | [\> | \<LL - | \      | \      | \<0 |
| (x10^9^/L)          | rease | ]{. | 0      | <0.75- | <0.5-0 | .25 |
|                     |       | und | .75xLL | 0.5xLL | .25xLL | xLL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }LL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Segmented           | Dec   | [\> | \<LL - | \      | \      | \<0 |
| Neutrophils         | rease | ]{. | 0      | <0.75- | <0.5-0 | .25 |
| (x10^9^/L)          |       | und | .75xLL | 0.5xLL | .25xLL | xLL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }LL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Bands/Stabs         | Inc   | [\< | \>UL - | \      | \>     | \>5 |
| Neutrophils         | rease | ]{. | 1      | >10.0- | 25.0-5 | 0.0 |
| (x10^9^/L)          |       | und | 0.0xUL | 2      | 0.0xUL | xUL |
|                     |       | erl |        | 5.0xUL |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }UL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     | \`    |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Lymphocytes         | Dec   | [\> | \<LL - | \      | \      | \<0 |
| (x10^9^/L)          | rease | ]{. | 0      | <0.75- | <0.5-0 | .25 |
|                     |       | und | .75xLL | 0.5xLL | .25xLL | xLL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }LL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Eosinophils         | Inc   | [\< | \>UL - | \      | \      | \>1 |
| (x10^9^/L)          | rease | ]{. | 2.5xUL | >2.5 - | >5.0-1 | 0.0 |
|                     |       | und |        | 5.0xUL | 0.0xUL | xUL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }UL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Platelets           | Dec   | [\> | \<LL - | \      | \<     | \<0 |
| (x10^9^/L)          | rease | ]{. | 0.5xLL | <0.5-0 | 0.33-0 | .15 |
|                     |       | und |        | .33xLL | .15xLL | xLL |
|                     |       | erl |        |        |        |     |
|                     |       | ine |        |        |        |     |
|                     |       | }LL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Prothrombin Time    | Inc   | [   | \>1.5- | \>2.0- | \>2.5- | \>  |
| (PT) (sec)          | rease | \<] | 2.0xUL | 2.5xUL | 3.0xUL | 3.0 |
|                     |       | {.u |        |        |        | xUL |
|                     |       | nde |        |        |        |     |
|                     |       | rli |        |        |        |     |
|                     |       | ne} |        |        |        |     |
|                     |       | 1.5 |        |        |        |     |
|                     |       | xUL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
|                     |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| Partial             | Inc   | [   | \>1.5- | \>2.0- | \>2.5- | \>  |
| Thromboplastin Time | rease | \<] | 2.0xUL | 2.5xUL | 3.0xUL | 3.0 |
| (PTT) (sec)         |       | {.u |        |        |        | xUL |
|                     |       | nde |        |        |        |     |
|                     |       | rli |        |        |        |     |
|                     |       | ne} |        |        |        |     |
|                     |       | 1.5 |        |        |        |     |
|                     |       | xUL |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+
| UL = upper limit of |       |     |        |        |        |     |
| normal range        |       |     |        |        |        |     |
|                     |       |     |        |        |        |     |
| LL = lower limit of |       |     |        |        |        |     |
| normal range        |       |     |        |        |        |     |
+---------------------+-------+-----+--------+--------+--------+-----+

Page 1 of 3

Appendix 4-14. WHO toxicity grading criteria for hematology and
biochemistry variables (Continued)

+-------------------+-------+-----+--------+--------+--------+-----+
|                   | DIRE  |     |        |        |        |     |
|                   | CTION |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| VARIABLE          | OF    | GR  | GRADE  | GRADE  | GRADE  | GR  |
|                   | C     | ADE | 1      | 2      | 3      | ADE |
|                   | HANGE | 0   |        |        |        | 4   |
+-------------------+-------+-----+--------+--------+--------+-----+
| LIVER FUNCTION    |       |     |        |        |        |     |
| TESTS             |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| SGOT (AST) (IU/L) | Inc   | [\  | \      | \>2.5- | \>5.0  | \   |
|                   | rease | <]{ | >1.25- | 5.0xUL | -10xUL | >10 |
|                   |       | .un | 2.5xUL |        |        | xUL |
|                   |       | der |        |        |        |     |
|                   |       | lin |        |        |        |     |
|                   |       | e}1 |        |        |        |     |
|                   |       | .25 |        |        |        |     |
|                   |       | xUL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| SGPT (ALT) (IU/L) | Inc   | [\  | \      | \>2.5- | \>5.0  | \   |
|                   | rease | <]{ | >1.25- | 5.0xUL | -10xUL | >10 |
|                   |       | .un | 2.5xUL |        |        | xUL |
|                   |       | der |        |        |        |     |
|                   |       | lin |        |        |        |     |
|                   |       | e}1 |        |        |        |     |
|                   |       | .25 |        |        |        |     |
|                   |       | xUL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| LDH (IU/L)        | Inc   | [\  | \      | \>2.5- | \>5.0  | \   |
|                   | rease | <]{ | >1.25- | 5.0xUL | -10xUL | >10 |
|                   |       | .un | 2.5xUL |        |        | xUL |
|                   |       | der |        |        |        |     |
|                   |       | lin |        |        |        |     |
|                   |       | e}1 |        |        |        |     |
|                   |       | .25 |        |        |        |     |
|                   |       | xUL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| Serum Alkaline    | Inc   | [\  | \      | \>2.5- | \>5.0  | \   |
| Phosphatase       | rease | <]{ | >1.25- | 5.0xUL | -10xUL | >10 |
| (IU/L)            |       | .un | 2.5xUL |        |        | xUL |
|                   |       | der |        |        |        |     |
|                   |       | lin |        |        |        |     |
|                   |       | e}1 |        |        |        |     |
|                   |       | .25 |        |        |        |     |
|                   |       | xUL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| Total Bilirubin   | Inc   | [\  | \      | \>2.5- | \>5.0  | \   |
| (mg/dL)           | rease | <]{ | >1.25- | 5.0xUL | -10xUL | >10 |
|                   |       | .un | 2.5xUL |        |        | xUL |
|                   |       | der |        |        |        |     |
|                   |       | lin |        |        |        |     |
|                   |       | e}1 |        |        |        |     |
|                   |       | .25 |        |        |        |     |
|                   |       | xUL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| Albumin (g/L)     | Dec   | [\> | \<LL - | \<     | \      | \<0 |
|                   | rease | ]{. | 0      | 0.85-0 | <0.70- | .55 |
|                   |       | und | .85xLL | .70xLL | 0      | xLL |
|                   |       | erl |        |        | .55xLL |     |
|                   |       | ine |        |        |        |     |
|                   |       | }LL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| Total Protein     | Dec   | [\> | \<LL - | \<     | \<     | \<0 |
| (g/L)             | rease | ]{. | 0      | 0.85 - | 0.70 - | .55 |
|                   |       | und | .85xLL | 0      | 0      | xLL |
|                   |       | erl |        | .70xLL | .55xLL |     |
|                   |       | ine |        |        |        |     |
|                   |       | }LL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   | Inc   | [\< | \>UL - | \>     | \>     | \>1 |
|                   | rease | ]{. | 1      | 1.15 - | 1.30-1 | .45 |
|                   |       | und | .15xUL | 1      | .45xUL | xUL |
|                   |       | erl |        | .30xUL |        |     |
|                   |       | ine |        |        |        |     |
|                   |       | }UL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| RENAL FUNCTION    |       |     |        |        |        |     |
| TESTS             |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| Blood Urea        | Inc   | [\  | \      | \>2.5- | \>5.0  | \   |
| Nitrogen (BUN)    | rease | <]{ | >1.25- | 5.0xUL | -10xUL | >10 |
| (mmol/L)          |       | .un | 2.5xUL |        |        | xUL |
|                   |       | der |        |        |        |     |
|                   |       | lin |        |        |        |     |
|                   |       | e}1 |        |        |        |     |
|                   |       | .25 |        |        |        |     |
|                   |       | xUL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| Creatinine        | Inc   | [\  | \      | \      | \>5.0  | \   |
| (micromol/L)      | rease | <]{ | >1.25- | >2.5 - | -10xUL | >10 |
|                   |       | .un | 2.5xUL | 5.0xUL |        | xUL |
|                   |       | der |        |        |        |     |
|                   |       | lin |        |        |        |     |
|                   |       | e}1 |        |        |        |     |
|                   |       | .25 |        |        |        |     |
|                   |       | xUL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
|                   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| Uric Acid         | Inc   | [\< | \>UL - | \>     | \>     | \>1 |
| (micromol/L)      | rease | ]{. | 1      | 1.15 - | 1.30-1 | .45 |
|                   |       | und | .15xUL | 1      | .45xUL | xUL |
|                   |       | erl |        | .30xUL |        |     |
|                   |       | ine |        |        |        |     |
|                   |       | }UL |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+
| UL = upper limit  |       |     |        |        |        |     |
| of normal range   |       |     |        |        |        |     |
|                   |       |     |        |        |        |     |
| LL = lower limit  |       |     |        |        |        |     |
| of normal range   |       |     |        |        |        |     |
+-------------------+-------+-----+--------+--------+--------+-----+

Page 2 of 3

**Appendix 4-14. WHO toxicity grading criteria for hematology and
biochemistry variables (Continued)**

+-------------+--------+------+---------+----------+----------+------+
|             | DIR    |      |         |          |          |      |
|             | ECTION |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| VARIABLE    | OF     | G    | GRADE 1 | GRADE 2  | GRADE 3  | G    |
|             | CHANGE | RADE |         |          |          | RADE |
|             |        | O    |         |          |          | 4    |
+-------------+--------+------+---------+----------+----------+------+
| E           |        |      |         |          |          |      |
| LECTROLYTES |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| Sodium      | De     | [\   | \<LL -  | \<       | \<0.93   | \    |
| (mmol/L)    | crease | >]{. | 0.96xLL | 0.96     | -0.89xLL | <0.8 |
|             |        | unde |         | -0.93xLL |          | 9xLL |
|             |        | rlin |         |          |          |      |
|             |        | e}LL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             | In     | [\   | \>UL -  | \>1.03   | \>1.07   | \    |
|             | crease | <]{. | 1.03xUL | -1.07xUL | -1.10xUL | >1.1 |
|             |        | unde |         |          |          | 0xUL |
|             |        | rlin |         |          |          |      |
|             |        | e}UL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| Potassium   | De     | [\   | \<LL -  | \<0.86 - | \<0.71 - | \    |
| (mmol/L)    | crease | >]{. | 0.86xLL | 0.71xLL  | 0.57xLL  | <0.5 |
|             |        | unde |         |          |          | 7xLL |
|             |        | rlin |         |          |          |      |
|             |        | e}LL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             | In     | [\   | \>UL-   | \>1.10 - | \>1.20 - | \    |
|             | crease | <]{. | 1.10xUL | 1.20xUL  | 1.40xUL  | >1.4 |
|             |        | unde |         |          |          | 0xUL |
|             |        | rlin |         |          |          |      |
|             |        | e}UL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| Calcium     | De     | [\   | \<LL -  | \<0.91 - | \<0.77 - | \    |
| (mmol/L)    | crease | >]{. | 0.91xLL | 0.77xLL  | 0.68xLL  | <0.6 |
|             |        | unde |         |          |          | 8xLL |
|             |        | rlin |         |          |          |      |
|             |        | e}LL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             | In     | [\   | \>UL -  | \>1.12 - | \>1.19 - | \    |
|             | crease | <]{. | 1.12xUL | 1.19xUL  | 1.31xUL  | >1.3 |
|             |        | unde |         |          |          | 1xUL |
|             |        | rlin |         |          |          |      |
|             |        | e}UL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| OTHERS      |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| Glucose     | De     | [\   | \<LL -  | \<0.77 - | \<0.59 - | \    |
| (fasting)   | crease | >]{. | 0.77xLL | 0.59xLL  | 0.44xLL  | <0.4 |
|             |        | unde |         |          |          | 4xLL |
| (mmol/L)    |        | rlin |         |          |          |      |
|             |        | e}LL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             | In     | [\   | \>UL -  | \>1.48 - | \>2.30 - | \    |
|             | crease | <]{. | 1.48xUL | 2.30xUL  | 4.59xUL  | >4.5 |
|             |        | unde |         |          |          | 9xUL |
|             |        | rlin |         |          |          |      |
|             |        | e}UL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| Amylase     | In     | [\   | \>UL -  | \>1.5 -  | \>2.0 -  | \    |
| (U/L)       | crease | <]{. | 1.5xUL  | 2.0 x UL | 5.0xUL   | >5.0 |
|             |        | unde |         |          |          | x UL |
|             |        | rlin |         |          |          |      |
|             |        | e}UL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
|             |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| Phosphorus  | De     | [\   | \<LL -  | \<0.8 -  | \<0.6 -  | \<0. |
| (mmol/L)    | crease | >]{. | 0.8xLL  | 0.6xLL   | 0.4xLL   | 4xLL |
|             |        | unde |         |          |          |      |
|             |        | rlin |         |          |          |      |
|             |        | e}LL |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+
| UL = upper  |        |      |         |          |          |      |
| limit of    |        |      |         |          |          |      |
| normal      |        |      |         |          |          |      |
| range       |        |      |         |          |          |      |
|             |        |      |         |          |          |      |
| LL = lower  |        |      |         |          |          |      |
| limit of    |        |      |         |          |          |      |
| normal      |        |      |         |          |          |      |
| range       |        |      |         |          |          |      |
+-------------+--------+------+---------+----------+----------+------+

Page 3 of 3

[^1]: ^a^ For graphical clarity only the higher anakinra doses of 0.4,
    1.0 and 2.0 mg/kg are shown. See Appendix 4-4 for a graph of the
    lower anakinra doses.