A randomized, controlled trial of interferon-?-1a (Avonex®) in patients with RA: a pilot study

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A randomized, controlled trial of interferon-?-1a (Avonex®) in patients

with rheumatoid arthritis: a pilot study [iSRCTN03626626]

Arthritis Res Ther 2004, 6:R73-R77

The electronic version of this article is the complete one and can be

found online at: http://arthritis-research.com/content/6/1/R73

Mark C Genovese1 , Eliza F Chakravarty1, Eswar Krishnan1 and Larry W

Moreland2

1Division of Immunology and Rheumatology, Stanford University, Palo

Alto, CA, USA

2Division of Rheumatology, University of Alabama at Birmingham,

Birmingham, AL, USA

© 2004 Genovese et al., licensee BioMed Central Ltd. This is an Open

Access article: verbatim copying and redistribution of this article are

permitted in all media for any purpose, provided this notice is

preserved along with the article's original URL.

Keywords: clinical trials, cytokines, interferon-?, rheumatoid

arthritis, therapy

The objective of this study was to evaluate the safety and possible

efficacy of IFN-?-1a for the treatment of patients with rheumatoid

arthritis (RA). Twenty-two patients with active RA were enrolled in a

phase II randomized, double-blind, placebo-controlled trial of 30 ?g

IFN-?-1a by weekly self-injection for 24 weeks. The primary outcome of

the study was safety. Secondary outcomes included the proportion of

patients achieving an American College of Rheumatology (ACR) 20 response

at 24 weeks. There were no significant differences in adverse events

reported in the two groups. Fewer than 20% of patients in each arm of

the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine

percent of patients receiving IFN-? and 67% receiving placebo terminated

the study early, most of them secondary to a perceived lack of efficacy.

Overall, IFN-?-1a had a safety profile similar to that of placebo. There

were no significant differences in the proportion of patients achieving

an ACR 20 response between the two groups.

Advances in the treatment of rheumatoid arthritis (RA) in the past

decade have resulted in significant improvements for many patients. The

advent of biologic response modifiers has changed the paradigm of

treatment options. However, despite the introduction of anti-cytokine

therapy, there remains a significant unmet need for additional therapy

in the treatment of RA that stems from several existing problems, namely

that no one therapy or combination of therapies works for all patients,

that patients who do respond rarely achieve remission, that therapy can

lose efficacy over time, and that side effects can limit the utility of

any therapy. These issues result in a demand for compounds that have

minimal side effects while providing disease modification both by

ameliorating signs and symptoms of RA and by retarding the erosion of

joint tissue.

Recombinant human IFN-? is approved by the US Food and Drug

Administration for the treatment of relapsing–remitting multiple

sclerosis [1]. Although its mechanism of action is poorly understood,

IFN-? is thought to antagonize the effects of IFN-? and other

proinflammatory cytokines, such as tumor necrosis factor and IL-1, and

to down-regulate T-cell activity [2-5]. Since these proinflammatory

cytokines and activated T cells are thought to mediate inflammation and

destruction of joint tissue in RA, there has been optimism that IFN-?

might be an efficacious therapy for human RA. Previously published

reports have suggested a possible improvement in patients with RA

treated with IFN-? [6,7]. Synovial biopsies in treated patients showed a

modest reduction in expression of inflammatory cytokines and

metalloproteinases [7].

We report a 24-week randomized, double-blind, placebo-controlled study

of the use of IFN-?-1a (Avonex®) in patients with RA. The primary

objective of the study was to evaluate the safety of its weekly

administration. Secondary objectives included the evaluation of its

potential efficacy in patients with RA who have active disease despite

treatment with available disease-modifying antirheumatic drugs (DMARDs).

This study was approved by the investigational review board at each

participating institution. The study subjects were men or women at least

18 years of age with RA defined by the American College of Rheumatology

(ACR) criteria [8]. All patients had failed at least one currently

available DMARD or biologic response modifier and had active RA with

more than six swollen and six tender joints at the time of enrollment.

Patients were allowed to be receiving the following background DMARDS,

if any, as long as the doses were stable for at least 2 months before

enrollment: methotrexate, sulfasalazine, and hydroxychloroquine either

as monotherapy or in combination. Patients taking up to 10 mg prednisone

daily and/or nonsteroidal anti-inflammatory drugs were allowed to

participate if the dose had been stable for 28 days before the screening

visit. All patients gave their written, informed consent prior to

participation. Exclusion criteria included a history of malignancy

within the past 5 years, a history of seizure disorder, and a positive

test for HIV, hepatitis B, or hepatitis C. Patients could be excluded

for active psychiatric disease, major organ dysfunction, or serious

local or systemic infection. Female patients were excluded if they were

pregnant, breastfeeding, or unwilling to use an adequate method of

contraception.

Treatments

Patients were randomized to receive IFN-?-1a (30 ?g intramuscular

weekly) or matched placebo in a 3:1 ratio at each of two sites (Stanford

University and the University of Alabama at Birmingham). The standard

dose of 30 ?g was chosen based upon its known profile in the treatment

of multiple sclerosis. All study personnel at both sites remained

blinded to the randomization schedule. The study drug and matched

placebo were provided in blinded fashion and were labeled with the

patient's name and randomization number. Physician's visits were

scheduled monthly. Patients who completed the study were seen again 4

weeks after the 24th injection (28 weeks) for a final visit.

Safety evaluation

Adverse events and safety issues pertaining to the use of IFN-? were

carefully monitored during the study.

Evaluation of efficacy

The primary efficacy end point of the study was a 20% improvement in ACR

criteria from baseline to week 24 [9]. The secondary end points were the

proportion of patients achieving a 50% or 70% ACR response at week 24.

Statistical methods

The differences between the randomization groups were evaluated by

Student's t-test (for differences in means) and chi-square test and

Fisher's exact test (for differences in proportions). Analysis of safety

end points included all patients who received at least one injection of

placebo or study drug. Differences in adverse events between the placebo

and interferon groups were analyzed using Fisher's exact test. The

primary analysis of efficacy end points was based on an

intention-to-treat (ITT) approach. All patients were analyzed according

to their randomization category. Those whose ACR response status could

not be ascertained because of a missing evaluation were considered

nonresponders for the relevant time point. The primary analysis of the

ACR response rates at week 24 was based on Fisher's exact test. A

one-tailed ? level of 0.05 was used for defining statistical significance.

Although the target accrual for the study was 40 patients, the total

number of patients screened was 25, with 22 patients enrolled (11 at

each site) over a period of 12 months. The anticipated accrual numbers

were not achieved because of difficulty recruiting. This difficulty

stemmed from the availability of other therapies approved by the US Food

and Drug Administration, the availability of other investigational

therapies, and patients' reluctance to give themselves intramuscular

injections.

The baseline demographics for this cohort were similar to those of other

previously published clinical trials [10,11]. Patients in the IFN-?-1a

treatment arm and the placebo arm were well matched for baseline

characteristics (Table 1), with the exception of a statistically

significant larger percentage of patients on background DMARDs in the

IFN-?-1a treatment arm (81%) than in the placebo arm (33%). The majority

(15/22; 68%) of patients in this study were on background DMARDs, with

methotrexate most commonly used. The majority of patients were women.

Disease activity was similar between the groups. The mean number of

tender joints in the treatment and placebo groups was, respectively, 20

and 25; the mean number of swollen joints, 16 and 19; and the mean

C-reactive protein, 2.4 and 1.6.

Of the 22 patients enrolled, only 7 completed the 24-week study.

Sixty-nine percent (11/16) receiving IFN-?-1a and 67% (4/6) patients

receiving placebo discontinued participation before 24 weeks. The median

duration of time in the study for both groups was 63.1 days. Of those

patients terminating the study before week 24, only two in the IFN-?-1a

arm and one in the placebo arm left the study secondary to adverse

events. The majority of patients leaving the study early did so

secondary to a perceived lack of efficacy: 8/11 (73%) of patients

enrolled in the IFN-?-1a group and 3/4 (75%) in the placebo group.

Safety

In general, IFN-?-1a was well tolerated in this RA population. There

were no serious adverse events during the study: no deaths,

malignancies, hospitalizations, or infections requiring intravenous

antibiotics occurred. No autoimmune events were reported. Three patients

left the study secondary to adverse events. One patient in each

treatment arm withdrew from the study secondary to symptoms of

depression. The third patient, who was in the IFN-?-1a group, withdrew

secondary to flu-like symptoms associated with the injection. No

statistically significant differences were seen in any of the adverse

events between the two treatment arms (Table 2). The most common adverse

events reported were flu-like symptoms associated with the

administration of the study drug; these included arthralgias, myalgias,

headache, fatigue, chills, and subjective fever.

Efficacy

The primary efficacy end point of the study was the ACR 20 response at

the completion of the 24-week study (Table 3). In the intention-to-treat

(ITT) responder-at-end-point analysis, 19% of patients in the IFN-?-1a

arm and 17% of patients in the placebo arm achieved an ACR 20 response

at 24 weeks, with only seven of 22 patients completing the 24-week

study. When using a more liberal, ITT last-observation-carried-forward

analysis, the ACR responder rates were higher, with the ACR 20 response

of 44% with IFN-?-1a and 33% with placebo (P = 0.52) (Table 3). In this

analysis, the last efficacy variables were used irrespective of study

completion status.

The goal of this study was to assess the effects of IFN-?-1a in the

treatment of RA. The decision to consider the use of this therapy in RA

was predicated on the well-known safety profile of the agent when used

in the treatment of multiple sclerosis [1] and on work that has

suggested a potentially beneficial role in the treatment of inflammatory

arthritis.

Prior studies utilizing IFN-? (Rebif®) for the treatment of

collagen-induced arthritis in rhesus monkeys suggested clinical

improvement in 75% of the animals treated and a notable decrease in the

C-reactive protein [6]. The same authors also demonstrated possible

benefits during a 12-week study in patients with active RA using

fibroblast IFN-? (Frone®). Of the 10 patients who completed this

open-label study, 4 achieved an ACR 20 response and the agent was

reportedly well tolerated. Additional work done with this same cohort

looking at the effects of IFN-? on synovial tissue showed interesting

results. Based on serial synovial biopsies before and during therapy,

there appeared to be a reduction of CD3+ T cells, reduced expression of

matrix metalloproteinase-1 and IL-1? at 1 month after therapy, as well

as a reduction of expression of IL-6 and IL-1? at 3 months [7]. This

study provided support for the hypothesis that IFN-? could result in

immunomodulation of RA and potentially lead to a reduction in symptoms

and increase in function in patients with RA.

The present study was designed to assess the effects of the use of

IFN-?-1a for the treatment of RA in a double-blind, placebo-controlled

fashion. The investigators initially planned to enroll 40 patients. This

number was based on the maximum number thought possible to enroll as

well as an appropriate number by which to assess safety parameters of

this agent for this indication. However, the investigators were unable

to meet this initial goal because of an inability to recruit patients to

participate. Several factors affected recruitment, including the

commercial availability of other biologic response modifiers, patients'

concerns regarding self-administration of an intramuscular injection,

and perception on the part of patients and referring physicians that

patients would develop side effects in the peri-injection period.

It is important to recognize that this study was not well powered to

address issues of efficacy. Although we did not achieved the desired

number of patients for this study, we did obtain important safety and

efficacy information.

The primary outcome of the study was safety. IFN-?-1a was generally well

tolerated by these RA patients. We did not see any serious safety

problems with the study drug and no serious adverse events were reported

as part of this study. There have been rare reports of autoimmune

phenomena developing in patients treated with IFN-? for multiple

sclerosis [12]. Although autoantibodies were not examined in this study,

no overt autoimmune events were reported. There were, however, adverse

events seen in this population (many of which were expected on the basis

of the known side effects of the study agent), including flu-like

symptoms occurring after the injections. The adverse events occurred

with similar frequency in patients receiving IFN-?-1a and those

receiving placebo. It is still possible that rare or uncommon adverse

events, including serious adverse events, are associated with the use of

IFN-? but were not detected in this small study.

The critical observation in this study was the degree of attrition, with

only 7 of 22 patients (32%) completing the study. The majority of

patients who did not complete the 24-week study terminated because of

perceived lack of efficacy rather than because of adverse events.

Irrespective of the study's power, the efficacy end point of a 20%

response defined by the ACR response criteria [9] with an ITT

responder-at-end-point analysis was quite low and was without a

clinically meaningful difference from that seen in the placebo group.

Using a more liberal ITT last-observation-carried-forward analysis, it

appears that 44% of patients were responding at the time of their last

visit but chose to leave the study anyway. The patients' decision to

terminate the study reflects either their perceptions of lack of

efficacy despite having achieved a 20% improvement in some cases or a

lack of improvement substantial enough to warrant continuing in the

study in the face of mild adverse events.

Conclusion

The results of this small pilot study suggest that IFN-?-1a, while

generally safe, may not be a significantly efficacious agent for the

treatment of RA. However, in order to definitively answer the question

as to whether IFN-?-1a has efficacy beyond that seen in placebo for the

treatment of RA, a larger and more appropriately powered study would be

required.

Competing interests

The authors received grant support and free drug and placebo from

Biogen, Cambridge, MA, USA.

Abbreviations

ACR = American College of Rheumatology; ACR 20 (50, 70) = 20% (50%, 70%)

improvement relative to baseline, according to ACR criteria; DMARD =

disease-modifying antirheumatic drug; IFN = interferon; IL =

interleukin; ITT = intention to treat; RA = rheumatoid arthritis.

Acknowledgement

This study was supported by grant support through Biogen. Study

medication was also provided by Biogen, Cambridge, Mass.

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