Date: February 3, 2003

From: Ellis F. Unger, M.D.

Team Leader

General Medicine Branch

Division of Clinical Trial Design and Analysis (DCTDA)

Office of Therapeutics Research and Review (OTRR)

Center for Biologics Evaluation and Research

U.S. Food and Drug Administration

Subject: Briefing Document for Arthritis Advisory Committee

Infliximab (Remicade®) and Congestive Heart Failure

Through: Marc Walton, M.D., Ph.D., Chief, General Medicine Branch, DCTDA

Karen Weiss, M.D., Director, DCTDA

####### Table of Contents

**Background [3](#background)**

Objectives [3](#objectives)

Primary Endpoint [3](#primary-endpoint)

Secondary Endpoints [3](#secondary-endpoints)

Study Design [3](#study-design)

Patient Selection [3](#patient-selection)

Inclusion Criteria [3](#inclusion-criteria)

Exclusion Criteria [4](#exclusion-criteria)

Study Procedures [4](#study-procedures)

Treatment Allocation, Blinding and Treatment
[4](#treatment-allocation-blinding-and-treatment)

Study Monitoring [4](#study-monitoring)

Study Outcomes [4](#study-outcomes)

Primary Efficacy Endpoint [4](#primary-efficacy-endpoint)

Secondary Efficacy Endpoints [5](#secondary-efficacy-endpoints)

Safety Endpoints [5](#safety-endpoints)

Statistical Plan [5](#statistical-plan)

Results [6](#results)

Subject Disposition [6](#subject-disposition)

Baseline Characteristics [6](#baseline-characteristics)

Concomitant Medications [8](#concomitant-medications)

Efficacy Results [9](#efficacy-results)

Primary Efficacy Endpoint: Clinical Status at Week 14
[9](#primary-efficacy-endpoint-clinical-status-at-week-14)

Secondary Endpoints [9](#secondary-endpoints-1)

Other Endpoints [10](#other-endpoints)

Salient Endpoints Beyond Week 14 [10](#salient-endpoints-beyond-week-14)

Efficacy Summary [11](#efficacy-summary)

Safety [11](#safety)

Deaths [11](#deaths)

Serious Adverse Events [11](#serious-adverse-events)

Acute Hemodynamic Effects [12](#acute-hemodynamic-effects)

Cardiovascular Adverse Events [12](#cardiovascular-adverse-events)

Safety Summary [12](#safety-summary)

Summary [12](#summary)

#  {#section .unnumbered}

## Background

Several lines of experimental evidence support a potential role of TNF-α
in the pathogenesis of congestive heart failure (CHF). Elevated
circulating levels of TNF-α have been associated with advanced CHF, and
TNF-α has been immunolocalized in cardiac myocytes of explanted hearts
from patients with dilated cardiomyopathy and ischemic heart disease.
TNF-α is also negatively inotropic *in vivo*, and can produce
cardiomyopathy and pulmonary edema in animal models. It has been
hypothesized that expression of cytokines such as TNF-α constitutes an
adaptive response to myocardial injury, and that TNF-α overexpression
may lead to deleterious cardiac remodeling with progressive left
ventricular (LV) dysfunction.

Centocor initiated a pilot study to explore the safety and biologic
effects of Infliximab in CHF: "A Phase II, Multicenter, Randomized,
Double-blind, Placebo-controlled Pilot Trial Evaluating the Effects of
Infliximab (Remicade^®^) in Patients with Stable Class III or IV
Congestive Heart Failure, Protocol C0168T30 ("ATTACH"). This document
summarizes the salient findings of the study.

## Objectives

### Primary Endpoint 

The primary objective was to evaluate the effect of Infliximab on
clinical status at 14 weeks.

### Secondary Endpoints

1\. combined risk of death and hospitalization for congestive heart
failure (CHF) through Week 14 and 28

2\. change in left ventricular ejection fraction (LVEF) at Week 14 and
Week 28

3\. changes in inflammatory markers (C-reactive protein \[CRP\], tumor
necrosis factor-alpha \[TNF-α\], interleukin-6 \[IL-6\])

4\. Physician Global Assessment at Week 14 and 28

## Study Design

A multicenter, randomized, double-blind, placebo-controlled trial to
assess the effects of Infliximab in patients with stable NYHA Functional
Class III or IV CHF. Subjects were to be randomized to infliximab 5
mg/kg, infliximab 10 mg/kg, or placebo. Randomization was 1:1:1. Test
agents were administered at three times: 0, 2, and 6 weeks
post-randomization. The duration of the study was 28 weeks.

## Patient Selection

### Inclusion Criteria

-   males and females, age ≥18

```{=html}
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```
-   stable New York Heart Association (NYHA) Functional Class (FC)
    III-IV CHF due to systolic dysfunction (stable ≡ no hospitalization
    for CHF, no change in FC, no receipt of intravenous CHF medication
    within 2 weeks prior to screening)

-   left ventricular ejection fraction (LVEF) ≤ 35% by radionuclide
    ventriculography

-   receiving treatment with a diuretic and an angiotensin converting
    enzyme (ACE) inhibitor (or angiotensin II antagonist)

### Exclusion Criteria

-   acute myocardial infarction (MI) or coronary revascularization
    within 2 months

-   hemodynamically significant obstructive valvular disease, cor
    pulmonale, restrictive or hypertrophic cardiomyopathy, constrictive
    pericarditis, congenital heart disease

-   resuscitation from sudden cardiac death (SCD) or implantable cardiac
    defibrillator (ICD) discharge within 3 months

-   receipt of non-steroidal anti-inflammatory drugs (NSAIDs) other than
    aspirin, positive inotropic agents other than digoxin, calcium
    antagonists other than amlodipine for hypertension (HTN) or angina,
    and class IC or III antiarrhythmic agents other than amiodarone

-   treatment with β-blocker, digoxin or spironolactone within 3 months
    unless ongoing and planned to be continued during the 28 week trial

-   chronic or recent infection, HIV positivity, presence of
    transplanted organ, malignancy within 5 years, lymphoproliferative
    disease, autoimmune disorder, other serious illness

## Study Procedures

### Treatment Allocation, Blinding and Treatment

Subjects were allocated to treatment by a central IVRS, and randomized
in the order they qualified. The three treatment groups were enrolled
concurrently. Unblinded pharmacists on site prepared blinded study
agents and were charged with maintaining the blind for other study
personnel. Results of assays of inflammatory markers were not provided
to the sites.

Eligible patients were randomized in equal proportions to placebo,
infliximab 5 mg/kg, or infliximab 10 mg/kg, each given as a 2-hour
intravenous infusion at Weeks 0, 2, and 6 post-randomization. Infliximab
infusions were capped at 1 gram.

### Study Monitoring

Subjects were evaluated at baseline, Week 1, 2, 6, 10, 14, 20, and 28
post-randomization. NYHA FC, history, physical exam, patient global
assessment, inflammatory markers, serum Infliximab level, adverse
events, and concomitant medication use were recorded at baseline and
each visit. Chest x-ray, 12-lead electrocardiogram (ECG), routine
hematology and chemistry labs, LVEF, Minnesota Living with Heart Failure
(MLWHF) questionnaire, and SF-36 health survey were evaluated at
baseline, Week 14 and 28.

## Study Outcomes

### Primary Efficacy Endpoint

The primary endpoint is a "clinical composite score," to be assessed at
Week 14, and defined as **improved**, **unchanged** or **worse**, based
on the following:

[Clinical Status is **worse** if the subject has]{.underline}:

-   died *or*

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```
-   been hospitalized for CHF (admitted at least overnight and received
    IV diuretics, vasodilators, or positive inotropic agents for
    treatment of CHF) *or*

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```
-   worsened NYHA FC *or*

```{=html}
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```
-   Patient Global Assessment judged to be moderately or markedly worse

[Clinical Status is **improved** if]{.underline}:

-   the Clinical Status is not worse *AND*

-   NYHA FC at 14 weeks is improved relative to baseline *or*

-   Patient Global Assessment is moderately or markedly improved

[Clinical Status is **unchanged**]{.underline} if it is neither better
nor worse.

The **Patient** **Global** **Assessment** represents the patient's
subjective assessment of their CHF status compared with Week 0,
according to the following categories: markedly improved, moderately
improved, mildly improved, unchanged, mildly worse, moderately worse,
markedly worse. The **Physician Global Assessment** is an identical
measure, but gauged by the physician.

### Secondary Efficacy Endpoints

1\. combined risk of death and hospitalization for CHF through 14 and 28
weeks

2\. ∆ LVEF; Week 14 ­­minus baseline; Week 28 minus baseline

3\. changes in inflammatory markers, compared with baseline, 2 hours
after initial infusion and Week 1, 2, 6, 10, 14, 20, and 28

4\. Physician Global Assessment at 14 and 28 weeks

### Safety Endpoints

1\. adverse events (AEs) through Week 14 and 28

2\. change in vital signs (VS) during infusions and for 2 hours
thereafter

3\. anti-infliximab antibodies at Week 20 and 28

4\. anti-double stranded DNA antibody at Week 28

5\. change in routine labs and ECG, compared with baseline, at Week 14
and 28

## Statistical Plan 

The test of statistical significance for the Week 14 clinical composite
score was an ordered alternative Cochran Mantel Haenszel Test with
scores of 1, 2 and 3 for worse, unchanged, and improved, respectively.
This was be performed as a 2-sided test at a 5% level of significance.
Also, the numbers of subjects with improved composite score at 14 weeks
were assessed using Fisher's Exact Test (2-sided, 5% significance
level).

A modified intent-to-treat (ITT) analysis was performed. Subjects who
withdrew consent, including consent to use their data, were not included
in analyses. For subjects with missing Week 14 data, a last observation
carried forward (LOCF) approach was used.

No interim analyses were planned or performed.

## Results

### Subject Disposition

A total of 150 subjects was enrolled at 32 study sites in the US from
August 14, 2000 to April 20, 2001. One subject randomized to 10 mg/kg
received 5 mg/kg.

![](media/image1.wmf){width="5.9534722222222225in"
height="1.9930555555555556in"}

## Baseline Characteristics

Table 2 provides a summary of baseline demographic characteristics and
cardiovascular disease status by treatment group. There was good balance
between treatment groups with respect to these factors, with the
exceptions of gender (24% females in the placebo group versus 15% in the
Infliximab groups) and NYHA FC IV (8% in the high-dose Infliximab group,
versus 4% in the other two groups). Of note, there was a trend in favor
of lower baseline BP in the Infliximab groups, as well as lower BP in
the 10 mg/kg group versus the 5 mg/kg group (mean systolic BP was 116,
113, and 110 in the placebo, 5 mg/kg and 10 mg/kg groups, respectively).

![](media/image2.wmf){width="5.9944444444444445in" height="6.16875in"}

Cardiovascular risk factors are summarized in Table 3. The 5 mg/kg
Infliximab group had a lower incidence of diabetes; other factors were
well-balanced between treatment groups.

### Concomitant Medications![](media/image3.wmf){width="5.616666666666666in" height="1.5770833333333334in"}

Concomitant medication use was similar across treatment groups (Table
4), although fewer subjects in the 5 mg/kg group were receiving digoxin
and beta-blockers at baseline. Overall, 97% of subjects were receiving a
diuretic, 81% were receiving an ACE inhibitor, 73% were receiving a
beta-blocker, and 38% were receiving an aldosterone
antagonist.![](media/image4.wmf){width="5.616666666666666in"
height="3.3631944444444444in"}

## Efficacy Results

### Primary Efficacy Endpoint: Clinical Status at Week 14

Clinical status is displayed in Figure 1. Slightly greater percentages
of subjects in the Infliximab groups showed improvement in clinical
status; however, this was offset by a higher percentage of subjects with
worse clinical status in the high-dose group. Differences between groups
were not statistically significant. Analysis of the individual
components of the composite endpoint showed that the trend towards
worsening of clinical status in the 10 mg/kg group was driven almost
entirely by CHF hospitalizations (8 subjects in the 10 mg/kg group,
versus 2 in each of the other two groups). There was also one death in
the high-dose group, and no deaths in either of the other
groups.![](media/image5.wmf){width="3.875in" height="2.525in"}

### Secondary Endpoints

#### Left Ventricular Ejection Fraction

Ejection fraction tended to increase in all 3 treatment groups. Over the
initial 14 weeks of the study, ∆ LVEF was 0.8, 3.5, and 2.1% in the
placebo, 5, and 10 mg/kg groups, respectively.

#### Physician Global Assessment

The physician global assessment at Week 14 was mildly, moderately, or
markedly improved in 41% and 45% of evaluated subjects in the low- and
high-dose Infliximab groups, respectively, compared to an assessment of
improved in 27% of placebo subjects. Four subjects in each group were
categorized as mildly worse, one subject in the 10 mg/kg group was
classed as moderately worse, and one subject in the high-dose group
died. No subjects were assessed as markedly worse.

#### All-cause mortality or CHF hospitalization

As noted above, there was one death in the 10 mg/kg Infliximab group.
Death was attributed to worsening CHF. Rates of all-cause mortality and
CHF hospitalization were 4.2 and 4.0% in the placebo and 5 mg/kg
Infliximab group, respectively (2 subjects in each group), and 20.9% in
the 10 mg/kg Infliximab group (8 subjects).

### Other Endpoints

#### New York Heart Association Functional Class

For subjects who were classified as NYHA FC III at screening
(practically all of the study population), approximately 25% were viewed
as improved to FC II at Week 14, and there were no notable inter-group
differences. One subject in the 10 mg/kg Infliximab group was
categorized as FC I. One subject in each of the Infliximab groups
declined to FC IV, and one subject in the 10 mg/kg group died.

#### Patient Global Assessment

Similar proportions of subjects considered themselves moderately or
markedly improved, and the placebo group had the greatest fraction of
subjects who considered themselves markedly improved. Generally, more
subjects in the Infliximab groups (relative to the placebo group)
considered their CHF to be mildly, moderately, or markedly worse.

### Salient Endpoints Beyond Week 14

#### Clinical Status (Week 28)![](media/image6.wmf){width="3.875in" height="2.5618055555555554in"}

Week 28 clinical status is summarized in Figure 2. At Week 28, there
tended to be fewer subjects with improved clinical statutes and more
subjects with worse clinical status in the Infliximab groups relative to
the placebo group. The trend toward a deleterious effect was
particularly apparent in the 10 mg/kg group, suggesting a dose-response
relation between Infliximab and harm.

#### 

#### All-cause mortality or CHF hospitalization (Week 28)

Between Week 14 and Week 28, there were 2 additional deaths in the 10
mg/kg group, and 1 death in the 5 mg/kg group, with no deaths in the
placebo group. Mortality rates for the placebo, 5 mg/kg, and 10 mg/kg
Infliximab groups were therefore 0%, 2%, and 6%, respectively, through
Week 28.

At Week 28, the percentages of subjects hospitalized for CHF were 10.5,
6.0, and 21.6%, and the corresponding rates for all-cause mortality or
CHF hospitalization were 10.5, 8.1, and 25.5%.

#### Physical Exam

Throughout the 28 weeks of the study, there were slight trends toward
weight gain in the Infliximab groups, and a slight trend in favor of
weight loss in the placebo group. There tended to be higher percentages
of subjects with worsened rales and worsened peripheral edema in the
Infliximab groups relative to the control group.

#### All-cause mortality (1 year)

One-year follow-up was complete for all subjects. Deaths and reported
cause of death are summarized in Table 5. Mortality rates through one
year were 8.2, 8.0, and 15.7% in the placebo, Infliximab 5 mg/kg, and 10
mg/kg groups, respectively. The Kaplan-Meier analysis (not shown)
suggests that death tended to occur earlier in both Infliximab-treated
groups. The two non-cardiovascular deaths in the 10 mg/kg Infliximab
group were attributed to pneumonia and sepsis.

### Efficacy Summary![](media/image7.wmf){width="5.163194444444445in" height="1.7402777777777778in"}

Infliximab at doses of 5 mg/kg and 10 mg/kg, administered at 0, 2, and 6
weeks, did not improve clinical status in patients with NYHA FC III and
IV CHF. There was increased risk of need for hospitalization for CHF and
increased mortality in Infliximab-treated subjects, particularly at the
higher dose.

## Safety

### Deaths

Deaths are briefly described under Efficacy Results, above. For all
patients who died, the mode of death was typical of the CHF patient
population.

### Serious Adverse Events

Through Week 28, cardiac failure was reported as a serious adverse event
(SAE) in 44%, 24%, and 8% of subjects in the Infliximab 10 mg/kg, 5
mg/kg, and placebo groups, respectively. Serious adverse events reported
in 2 (4%) subjects in the high-dose Infliximab group and in none of the
other groups included: increased creatinine phosphokinase, hypotension,
myalgia, and myocardial infarction.

### Acute Hemodynamic Effects

Of note, Infliximab had acute effects on BP. The proportions of subjects
with decreased systolic BP were greater in the 5 mg/kg Infliximab (55%)
and 10 mg/kg Infliximab (44%) groups compared with the placebo group
(17%). Corresponding decreases in diastolic BP were observed as well:
24%, 18%, and 8%, respectively.

### Cardiovascular Adverse Events

Analysis of cardiovascular adverse event rates has the potential to
provide clues to help elucidate the mechanism(s) of potentially
deleterious action(s) of Infliximab in CHF. Major factors to consider in
the CHF patient population include: 1) genesis of arrhythmias; 2)
hemodynamic effects; 3) exacerbation of ischemia; and 4) negative
inotropism. Adverse events most relevant to CHF are summarized in Table
6.

![](media/image8.wmf){width="5.4in" height="2.4402777777777778in"}

There are trends favoring excess dizziness, dyspnea, hypotension, and
angina in the Infliximab treatment groups. Of note, dizziness was
largely delayed, and not related to the infusion of the agent, per se,
despite the apparent acute BP-lowering effect of Infliximab.

### Safety Summary

Infliximab was associated with increased risk of death and
hospitalization for CHF, as described under Efficacy Results. Consistent
with these findings, there are trends favoring excess dizziness,
dyspnea, hypotension, angina, and myocardial infarction in the
Infliximab treatment groups. The patterns of deaths, physical findings,
and adverse events do not suggest a specific mechanism through which
Infliximab exerts deleterious effects in patients with CHF.

## Summary

ATTACH was a small-sized, multicenter, randomized, double-blind,
placebo-controlled dose-ranging, "add-on" study of Infliximab in CHF.
The investigation enrolled patients who were NYHA FC III-IV with an EF
of ≤ 35%. The study failed on its efficacy endpoints, and Infliximab
appeared to show harm, as evidenced by excess death and requirement for
hospitalization for CHF in the 10 mg/kg group. Although the prespecified
endpoints of death and CHF hospitalization were not increased in the 5
mg/kg Infliximab group, there are clues in the patterns of adverse
events that suggest deleterious effects of Infliximab, even at the lower
dose. The limited sample size does not make it possible to distinguish
between the two doses, and there is no basis to conclude that the 5
mg/kg does not increase mortality.

The study was not designed to assess the effect of Infliximab in milder
forms of CHF (NYHA FC I and II), and no conclusions can be drawn
regarding the safety of Infliximab in milder forms of CHF.

The patterns of deaths, physical findings, and adverse events do not
suggest a unifying mechanism of action leading to harmful effects in the
CHF population. The study was too small to provide insight into specific
CHF subgroups at particular risk of adverse outcomes with Infliximab.