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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A:

Objective

To demonstrate the long-term efficacy of anakinra, a human recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long-term safety of anakinra at different daily doses.

Methods

The efficacy and safety of anakinra were previously demonstrated in a double-blind, placebo-controlled, 24-week evaluation in 472 patients with active RA. Of 345 patients who completed the placebo-controlled phase of the study, 309 continued in a 52-week, multicenter, double-blind, parallel-group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52-week extension phase (76 weeks total exposure).

Results

A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24-week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment-related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy.

Conclusion

The clinical benefits of treatment with daily self-administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long-term use of anakinra for the treatment of patients with RA.

The proinflammatory cytokines, tumor necrosis factor α (TNFα), interleukin-1α (IL-1α), and IL-1β, have a central role in the pathogenesis of rheumatoid arthritis (RA) (1–4). These macrophage- and fibroblast-derived cytokines are important mediators of cartilage and bone destruction in RA, as well as mediators of immune reactions and local and systemic inflammation. Although IL-1 and TNFα share many biologic actions that are relevant in RA (4–6), research in animal models of arthritis suggests that IL-1 is the dominant cartilage-destructive cytokine (7). The biologic effects of both cytokines are modulated in vivo by naturally occurring protein inhibitors (8, 9), and both have become prime targets for biologic therapy in RA (10–16).

IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1 (17) that competes for the IL-1 receptor and thereby prevents IL-1 signaling. Levels of IL-1Ra are increased in patients with RA, although the relative increase in the level of IL-1Ra in comparison with IL-1 appears insufficient to prevent IL-1 signaling (18). Thus, supplementation of IL-1Ra levels is one possible therapeutic intervention for RA patients.

Anakinra, a recombinant-methionyl human IL-1Ra, is a unique and targeted 153–amino acid polypeptide with a molecular mass of 17.3 kd and 19% and 26% amino acid sequence identity with human IL-1α and IL-1β, respectively. It has binding affinities similar to those of native IL-1Ra, IL-1α, and IL-1β for the type I IL-1 receptor on T lymphocytes, synovial cells, and chondrocytes (19), and its plasma half-life following a single subcutaneous (SC) injection in patients with RA is 6 hours (20). Anakinra has been shown to reduce joint inflammation and swelling, cartilage destruction, and bone resorption in several animal models of RA (2, 21).

Following the demonstration of short-term efficacy and safety in a preliminary double-blind, dose-ranging study in patients with RA (15), the safety and efficacy of daily SC injections of anakinra was confirmed in a large, multicenter, placebo-controlled, 24-week study (16). In addition to demonstrating significant improvements in the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) composite index (22) and the Paulus 20% criteria (23), this study also provided evidence of retardation in the rate of radiographically observed structural damage (16, 24). Anakinra is currently the only biologic agent that specifically inhibits IL-1–mediated synovial inflammation and articular destruction.

We now report the results of a 52-week, double-blind, parallel-group extension trial in 309 of the 345 patients completing the original study, who received daily SC injections of anakinra for a total exposure of 76 weeks.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A:

Patients.

As previously reported (16), 345 of the 472 patients who entered the 24-week, placebo-controlled, double-blind, randomized trial of anakinra completed the study. Of these 345 patients, 309 entered a 52-week extension phase. Patients who had received anakinra for the first 24 weeks continued receiving it at the same daily dose (30 mg, 75 mg, or 150 mg), and those who had received placebo for the first 24 weeks were randomized to receive either 30 mg, 75 mg, or 150 mg of anakinra during the extension phase (Figure 1). The study was designed to allow both patients and investigators to remain blinded to the dose and study medication. Neither the patients nor the investigators were aware of which subjects had switched from placebo to anakinra, which patients continued to receive anakinra, and which dose of anakinra each patient was receiving. Patients from 36 centers in 11 European countries were included. All patients met the ACR criteria for the classification of RA (25), and all had a disease duration of at least 12 months but less than 8.5 years. Details of the clinical characteristics of the patients at the time of entry in the placebo-controlled, randomized clinical phase and details of exclusion criteria have been previously reported (16).

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Figure 1. Study schema.

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Study medication.

Anakinra (Amgen, Thousand Oaks, CA) was produced by recombinant DNA technology using Escherichia coli fermentation. Anakinra is identical to the naturally occurring nonglycosylated human form of IL-1Ra, with the exception of 1 N-terminal methionine. Study medication was packaged as single-use, unit-dose vials. Each vial contained 1.25 ml of solution consisting of anakinra (at a concentration of 30 mg, 75 mg, or 150 mg/ml), sodium chloride, sodium citrate, polysorbate 80, EDTA, citric acid, and sterile water for daily SC injection. The same constituents, without the addition of anakinra, were used to formulate the placebo solution. As in the earlier study, patients were instructed to rotate the injection site between the abdomen, thighs, and the back of the upper arms.

Efficacy evaluation.

The analytic subset for the efficacy evaluation comprised the 309 patients who participated in the extension phase of the study. The primary efficacy measure was the proportion of patients who attained a response according to the ACR 20% criteria (ACR20) (22), as assessed at week 48 (24 weeks into the extension phase). Sustained ACR20 responders were subjects who satisfied the ACR20 criteria on at least 4 of 6 monthly evaluations and had at least 1 response at week 36 or 48.

ACR50 and ACR70 responses were also assessed at week 48. Ten secondary clinical efficacy measures were evaluated at week 48 and included change from baseline in the number of swollen joints and the number of tender joints, patient's assessment of disease activity (0–4 scale), investigator's assessment of disease activity (0–4 scale), patient's assessment of pain (visual analog scale), Health Assessment Questionnaire (HAQ) score (26), level of C-reactive protein, and Westergren erythrocyte sedimentation rate. All clinical efficacy measurements except the HAQ score were obtained at weeks 24, 28, 32, 36, 40, 44, and 48; the HAQ score was measured at weeks 24 and 48. Efficacy assessments for patients who crossed over from placebo to anakinra in the extension phase were analyzed separately. Radiographs of the hands and wrists were obtained at weeks 24 and 48. Changes from baseline in joint space narrowing, erosions, and the number of patients with new erosions were assessed, using the methods of Genant (27) and Larsen (28), by experienced skeletal radiologists blinded to both the treatment group and the time of radiography. Results of the radiographic assessments were published separately (24).

Safety evaluation.

The analytic subset for the safety evaluation comprised all 472 patients who participated in the 24-week placebo-controlled phase and included the data (through week 76) of the 309 patients who participated in the extension phase. Safety assessments were completed at every visit through week 76. These included standardized assessments of reported adverse events; examination of vital signs; inspection of injection sites for the presence of erythema, edema, or other abnormalities; and evaluation of laboratory data (complete blood cell count, urinalysis, renal and liver function tests). Adverse events were defined as any clinical abnormality reported following direct questioning, and these were graded for severity according to US Food and Drug Administration guidelines. According to the study protocol, discontinuation was required if the total white blood cell count decreased below 3.5 × 109/liter or the absolute neutrophil count decreased below 2 × 109/liter. All patients who received at least 1 injection of anakinra were included in the safety analyses.

Statistical analysis.

To determine the ACR20, ACR50, and ACR70 composite scores, including the sustained ACR20 response, nonresponder imputation was used for missing or unevaluable ACR20 responses.

To determine the individual ACR end points, the last available value (last observation carried forward method) was used as the 48-week value for subjects who withdrew from treatment or whose data were not available at any time during the study. To assess changes between week 24 and week 48, the treatments were compared by matched pair tests (McNemar's test, paired t-test, or Wilcoxon's signed rank test), as appropriate. The statistical null hypothesis for the primary outcome measure of efficacy was that the proportion of patients achieving an ACR20 response after 24 weeks of treatment in the extension phase would be the same as that at the time of entry in the study (i.e., after completing 24 weeks in the placebo-controlled phase) (16).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A:

Study population.

Of the 472 patients enrolled in the placebo-controlled phase of the study, 345 (73%) completed the 24-week trial. A total of 309 of the completers (90%) entered the 52-week extension phase; of these subjects, 218 (71%) completed all 76 weeks, and 91 (29%) withdrew prematurely. The withdrawal rate was similar in all treatment groups.

Of the patients entering the extension phase, 233 had received anakinra during the original 24-week study (81, 79, and 73 patients, respectively, received 30 mg, 75 mg, and 150 mg daily), and 76 had received placebo. For the extension phase, this latter group was rerandomized to receive 30 mg, 75 mg, or 150 mg of anakinra (30, 24, and 22 patients, respectively). Baseline and clinical characteristics (Tables 1 and 2) of the patients entering the extension phase were similar to those of patients who entered the original placebo-controlled trial.

Table 1. Characteristics of patients entering the extension phase*
CharacteristicExtension phasePlacebo-controlled phase
Placebo to anakinra (n = 76)Anakinra to anakinra (n = 233)Placebo (n = 121)Anakinra (n = 351)
  • *

    RA = rheumatoid arthritis; DMARDs = disease-modifying antirheumatic drugs; NSAID = nonsteroidal antiinflammatory drug.

Age, years, mean ± SD53.1 ± 11.352.7 ± 13.652.2 ± 11.953.4 ± 13.2
F/M, %69.7/30.376.8/23.270.2/29.876.6/23.4
Weight, kg, mean ± SD69.7 ± 13.969.9 ± 15.069.1 ± 14.369.8 ± 14.6
Duration of RA, years, mean ± SD3.7 ± 2.54.1 ± 2.43.7 ± 2.44.1 ± 2.4
Rheumatoid factor positive, %68.469.569.469.5
Previous use of DMARDs, %73.771.780.073.5
No. of previous DMARDs used, mean ± SD1.2 ± 1.01.2 ± 1.01.3 ± 0.91.3 ± 1.0
NSAID use, %89.583.787.682.1
Corticosteroid use, %40.847.639.743.6
Erosive disease, %73.774.274.473.2
Table 2. Clinical and laboratory characteristics of patients entering the extension phase*
 Extension phasePlacebo-controlled phase
Placebo to anakinra (n = 76)Anakinra to anakinra (n = 233)Placebo (n = 121)Anakinra (n = 351)
  • *

    Values are the mean ± SD.

No. of tender joints32.7 ± 13.633.7 ± 12.932.8 ± 14.134.8 ± 13.8
No. of swollen joints24.5 ± 8.626.4 ± 9.625.6 ± 10.326.3 ± 9.8
Investigator global assessment of disease activity3.0 ± 0.43.1 ± 0.43.0 ± 0.43.1 ± 0.4
Patient global assessment of disease activity3.0 ± 0.53.1 ± 0.53.0 ± 0.53.1 ± 0.5
Pain on visual analog scale (0–1 cm)0.6 ± 0.170.62 ± 0.190.6 ± 0.20.6 ± 0.2
Health Assessment Questionnaire score1.5 ± 0.61.5 ± 0.71.5 ± 0.61.6 ± 0.7
C-reactive protein level, mg/dl3.59 ± 3.903.98 ± 3.794.24 ± 4.164.10 ± 3.81
Erythrocyte sedimentation rate, mm/hour43.1 ± 28.350.0 ± 29.846.8 ± 29.550.4 ± 29.1
Duration of morning stiffness, minutes/day125.7 ± 89.2135.5 ± 103.4127 ± 91.5136.2 ± 103.6
Rheumatoid factor, IU/ml230.1 ± 281.9265.3 ± 332.1  

Efficacy over 48 weeks.

The results of the primary outcome measure (the change in ACR20 response at week 48) are presented in Table 3. The efficacy of anakinra demonstrated at 24 weeks (16) was maintained at 48 weeks. Forty-six percent of patients continuing all doses of anakinra demonstrated an ACR20 response at 48 weeks, which was similar to the 51% of patients who demonstrated an ACR20 response at 24 weeks (Table 3). For the individual doses of anakinra, 41–51% of patients demonstrated ACR20 responses at 48 weeks, compared with 47–53% at 24 weeks. A dose response was not evident in either 24-week period. At 48 weeks, ACR50 and ACR70 responses were demonstrated in 18% and 3%, respectively, of patients who continued all doses of anakinra, which was similar to the 21% and 3% of patients who demonstrated these responses at 24 weeks (16) (data not shown). Forty-two percent of patients receiving all doses of anakinra demonstrated a sustained ACR20 response at 48 weeks, compared with 36% at 24 weeks (Table 4).

Table 3. Patients achieving an ACR20 response following 24 weeks of treatment with anakinra during the extension phase (weeks 24–48)*
 Placebo to anakinraAnakinra to anakinra
All doses (n = 76)30 mg (n = 30)75 mg (n = 24)150 mg (n = 22)All doses (n = 233)30 mg (n = 81)75 mg (n = 79)150 mg (n = 73)
  • *

    Values are the number (%) of patients. P values represent 24 weeks versus 48 weeks, by McNemar's test. ACR20 = American College of Rheumatology 20% criteria for improvement (see ref. 22).

Week 2426 (34)11 (37)6 (25)9 (41)118 (51)42 (52)37 (47)39 (53)
Week 4839 (51)14 (47)11 (46)14 (64)107 (46)33 (41)40 (51)34 (47)
P0.0070.450.060.180.220.090.660.41
Table 4. Patients achieving a sustained ACR20 response during 48 weeks of anakinra therapy*
 Placebo to anakinraAnakinra to anakinra
All doses (n = 76)30 mg (n = 30)75 mg (n = 24)150 mg (n = 22)All doses (n = 233)30 mg (n = 81)75 mg (n = 79)150 mg (n = 73)
  • *

    Values are the number (%) of patients. P values represent 24 weeks versus 48 weeks, by McNemar's test. ACR20 = American College of Rheumatology 20% criteria for improvement (see ref. 22).

Week 2411 (14.5)6 (20.0)2 (8.3)3 (13.6)84 (36.1)32 (39.5)29 (36.7)23 (31.5)
Week 4830 (39.5)10 (33.3)9 (37.5)11 (50.0)97 (41.6)34 (42.0)32 (40.5)31 (42.5)
P< 0.0010.2190.0160.0220.1180.8320.6070.134

The long-term maintenance of response to anakinra was also evident in the individual components of the ACR criteria, as shown in Table 5. The exception was the HAQ, which showed a small but statistically significant deterioration during the second 24 weeks of treatment. Across the individual dose groups, patients' global assessment and assessment of pain, and the HAQ showed some deterioration at the 150-mg dose. The decline in HAQ was <0.22, which has been established as the minimal change that is clinically meaningful (29).

Table 5. Changes in ACR component outcome measures during the second 6 months of treatment with anakinra during extension study*
Outcome measurePlacebo to anakinraAnakinra to anakinra
All doses (n = 76)30 mg (n = 30)75 mg (n = 24)150 mg (n = 22)All doses (n = 233)30 mg (n = 81)75 mg (n = 79)150 mg (n = 73)
  • *

    Values are the mean ± SEM. ACR = American College of Rheumatology.

  • P < 0.001 by paired t-test.

  • P < 0.05 by paired t-test.

  • §

    P < 0.005 by paired t-test.

No. of swollen joints−4.1 ± 1.1−3.2 ± 2.1−5.0 ± 2.1−4.4 ± 1.2§−0.9 ± 0.5−0.3 ± 0.9−1.5 ± 0.9−0.9 ± 1.1
No. of tender joints−5.6 ± 1.3−5.2 ± 2.6−6.1 ± 1.9§−5.5 ± 1.8−0.2 ± 0.9−0.3 ± 1.2−1.2 ± 1.8+1.0 ± 1.6
Patient global assessment−0.3 ± 0.1−0.2 ± 0.2−0.3 ± 0.1−0.3 ± 0.2+0.1 ± 0.1+0.1 ± 0.10.0 ± 0.1+0.2 ± 0.1
Investigator assessment−0.3 ± 0.1−0.4 ± 0.2−0.3 ± 0.1−0.2 ± 0.20.0 ± 0.10.0 ± 0.10.0 ± 0.10.1 ± 0.1
Pain assessment−0.09 ± 0.03§−0.08 ± 0.04−0.07 ± 0.05−0.12 ± 0.07+0.03 ± 0.02+0.04 ± 0.03−0.01 ± 0.03+0.07 ± 0.03
Health Assessment Questionnaire−0.26 ± 0.05−0.33 ± 0.1§−0.11 ± 0.1−0.35 ± 0.1§+0.06 ± 0.03+0.08 ± 0.05−0.01 ± 0.04+0.1 ± 0.05
C-reactive protein level, mg/dl−1.0 ± 0.3§−1.2 ± 0.5−0.8 ± 0.5−1.1 ± 0.6+0.02 ± 0.2−0.02 ± 0.3−0.07 ± 0.3−0.01 ± 0.3
Erythrocyte sedimentation rate, mm/hr−11.9 ± 2.2−11.9 ± 3.4§−15.0 ± 3.4−8.2 ± 4.9−1.7 ± 1.4−1.3 ± 2.3−3.2 ± 2.0−0.5 ± 2.9

Fifty-one percent of patients receiving placebo who were randomized to all doses of anakinra demonstrated an ACR20 response at 48 weeks (P = 0.007), compared with 34% at 24 weeks. For the individual doses of anakinra, an ACR20 response was demonstrated in 46–64% of patients (Table 3). A dose response was not evident. ACR50 and ACR70 responses were demonstrated in 20% and 1% of these patients, respectively, at 48 weeks, compared with 12% and 1% at 24 weeks. Among the patients who originally received placebo and were randomized to all doses of anakinra, 40% demonstrated a sustained ACR20 response at 48 weeks, compared with 15% at 24 weeks (P < 0.001) (Table 4). For the individual doses of anakinra, a sustained ACR20 response was demonstrated in 33–50% of these patients at 48 weeks, compared with 8–20% at 24 weeks (anakinra 75 mg/day, P = 0.016; 150 mg/day, P = 0.022). The improvements in the ACR composite results parallel improvements in the secondary efficacy measures (Table 5) and were very similar to the improvements demonstrated by patients receiving anakinra during the original placebo-controlled trial (16). The rapid improvements in acute-phase reactants demonstrated in these patients following the switch from placebo to anakinra therapy were similar to the improvements seen in the active treatment groups in the placebo-controlled phase of the trial (Figure 2). Improvements in all ACR components were statistically significant for the combined cohort of patients that switched from placebo to anakinra and for some of the parameters in the individual dose groups, despite the small sample sizes (Table 5).

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Figure 2. Changes in C-reactive protein levels (mg/dl) during 48 weeks of therapy with anakinra. Bars show the mean ± SEM.

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Long-term safety and tolerability.

The safety and tolerability of daily SC administration of anakinra were evaluated over 76 weeks (28 weeks beyond the point to which efficacy was assessed). The rates of adverse event were adjusted for exposure to study medication to allow comparison with rates in the placebo group during the first 24 weeks of the study.

Overall, anakinra was well tolerated at doses of 30 mg, 75 mg, and 150 mg, for up to 76 weeks. The rates of withdrawal during the extension phase were similar to those during the placebo-controlled phase (16) (Table 6). Rates of withdrawal due to adverse events in the extension phase (15%) were similar to those in the first 24 weeks of therapy (17%; Table 6). Most withdrawals were related to worsening RA. The next most common reason for withdrawal was hematologic changes which, according to the study protocol, required withdrawal from the study. Subjects who withdrew because of hematologic changes included 6 patients with decreases in white blood cell counts and 1 patient in whom eosinophilia developed. During the first 6 months of study, granulocytopenia and eosinophilia were each reported in 17 patients receiving anakinra (adjusted rate of 0.4 for each event) but in no patient receiving placebo.

Table 6. Adverse events and withdrawals from the study*
 Extension phasePlacebo-controlled phase
Placebo to anakinra (n = 76)Anakinra to anakinra (n = 233)Total (n = 309)Placebo (n = 121)Anakinra (n = 351)
  • *

    Values are the no. (%).

Total withdrawals21 (28)70 (30)91 (29)39 (32)88 (25)
 Adverse event14 (18)32 (14)46 (15)24 (20)59 (17)
 Lack of efficacy4 (5)22 (9)26 (8)11 (9)15 (4)
 Other3 (4)16 (7)19 (6)4 (3)16 (5)
Most common adverse events leading to withdrawal     
 Arthritis flare4 (5.2)14 (6.0)18 (5.8)17 (14.0)31 (8.8)
 Leukopenia1 (1.3)4 (1.7)5 (1.6)0 (0.0)1 (0.3)
Other notable adverse events     
 Infection1 (1.3)3 (1.3)4 (1.3)1 (0.8)4 (1.1)
 Malignancy1 (1.3)1 (0.4)2 (0.65)0 (0.0)2 (0.6)

The decreases in neutrophils and platelets seen in patients receiving anakinra were consistent with changes attributable to the antiinflammatory action of the drug, and no clinical events were associated with observed granulocytopenia in the patients who withdrew as required by protocol when the neutrophil count decreased below 2 × 109 cells/liter.

The only side effects that appeared to be closely linked with administration of anakinra were skin reactions at the injection site (Table 7). Such reactions were the most frequent adverse events, and their frequency and severity increased with increasing doses of anakinra. Following adjustment for drug exposure time, the frequency of injection site reactions (ISRs) was 0.82 per patient-year of exposure in the placebo group (first 24 weeks) and 1.01, 2.43, and 3.73 for the 30-mg, 75-mg, and 150-mg doses of anakinra, respectively (long-term rates). A life-table analysis of patients experiencing ISRs showed that patients were likely to have their first ISR within the first 30 days of treatment. Patients who had not experienced an ISR after 30 days of treatment were unlikely to have an ISR after more prolonged treatment (data not shown). Most ISRs were mild or moderate, even in the higher-dose groups, and none resulted in any serious complications. The most common symptoms and signs at the injection site were erythema, pruritus, and rash. The number of patients with severe ISRs decreased after the first 24 weeks of therapy, from 11 anakinra patients (3.1%) in the first 6 months to 2 patients (0.6%) during the extension phase. After the first 24 weeks of therapy, there were no withdrawals attributable to ISRs.

Table 7. Exposure-adjusted adverse events most commonly reported during the 76-week study*
Adverse eventPlacebo (n = 121)Anakinra
30 mg (n = 149)75 mg (n = 140)150 mg (n = 138)Total (n = 427)
  • *

    Values are the number of subjects reporting the event (number of occurrences per subject-year of exposure). Patients received anakinra during both study periods.

Injection site reaction30 (0.82)71 (1.01)101 (2.43)110 (3.73)282 (2.00)
Rheumatoid arthritis flare40 (1.05)56 (0.49)48 (0.43)40 (0.38)144 (0.44)
Arthralgia15 (0.37)25 (0.21)18 (0.15)17 (0.15)60 (0.17)
Abdominal pain6 (0.14)23 (0.19)14 (0.12)21 (0.19)58 (0.16)
Arthritis2 (0.05)13 (0.10)16 (0.13)18 (0.16)47 (0.13)
Influenza-like symptoms7 (0.16)12 (0.09)22 (0.19)12 (0.11)46 (0.13)
Upper respiratory8 (0.19)13 (0.10)15 (0.13)17 (0.15)45 (0.12)
Pruritus6 (0.14)12 (0.09)12 (0.10)8 (0.07)32 (0.09)
Diarrhea6 (0.14)12 (0.09)13 (0.10)6 (0.05)31 (0.08)
Rhinitis3 (0.07)10 (0.08)13 (0.10)8 (0.07)31 (0.08)

Other than ISRs, the most commonly observed adverse events were related to worsening RA (Table 7), and these events occurred more frequently in the placebo group. Two deaths, which were considered by the investigators to be unrelated to the study medication, occurred during or shortly after extended therapy with 75 mg of anakinra. The exposure-adjusted incidences of infection were 1.40, 0.91, 1.0, and 1.1 subjects per patient-year of exposure in the placebo, 30-mg, 75-mg, and 150-mg groups, respectively. Events that were life-threatening or required hospitalization appeared to be randomly distributed across treatment groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A:

This report describes the clinical outcomes and safety profiles of patients who received anakinra therapy for up to 76 weeks. The study comprised an initial 24-week, placebo-controlled, randomized trial and a 1-year, non–placebo-controlled extension phase. Two hundred thirty-three patients who had been treated with anakinra in the original study continued to receive 30 mg, 75 mg, or 150 mg of anakinra, and 76 patients who had received placebo during the first 24 weeks were rerandomized to receive either 30 mg, 75 mg, or 150 mg of anakinra. All patients had active RA, with a mean disease duration of <4.0 years.

Patients continued to respond to anakinra during all 48 weeks of efficacy evaluation, with the proportion of patients achieving ACR20 remaining relatively unchanged during the first and second 6 months of therapy (51% and 46%, respectively). At 48 weeks, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued receiving anakinra (all doses). The analysis of sustained response confirmed that the improvements observed in the first 24 weeks were maintained during the extension phase. Long-term maintenance of response was also demonstrated by the continued benefit observed in the individual outcome measures. Data from patients who received placebo during the first 24 weeks and were randomized to receive anakinra therapy during the second 24 weeks confirmed the efficacy of anakinra. These patients showed a significant increase in the ACR20 response (from 34% to 51%) and also maintained a sustained response during the time they were receiving anakinra. Among patients who originally received placebo and were randomized to all doses of anakinra, 20% and 1%, respectively, demonstrated ACR50 and ACR70 responses at 48 weeks.

As previously described (24), the slowing of radiologic progression, demonstrated in the placebo-controlled portion of the study (16), was maintained in the patients who continued to receive anakinra therapy for an additional 6 months. The observation that treatment with anakinra slows cartilage loss in patients with RA, even when the ACR20 response is modest, is consistent with observations in animal models of inflammatory arthritis, which suggest that IL-1 plays a critical role in cartilage destruction (7).

The results of this extension study confirm that anakinra, self-administered by daily SC injection by patients with RA, is well tolerated and safe. The data show that following 76 weeks of therapy, the most frequently reported adverse events were dose-related mild, localized, and transient ISRs. These reactions rarely occurred after the first 30 days of therapy, and none of the patients participating in the extension phase of the study withdrew because of ISRs. No deaths attributable to the study medication or serious life-threatening adverse events occurred, but 4 patients withdrew because of infection. For 5 patients, withdrawal was required according to the study protocol (neutrophil count lower than 2 × 109/liter). No evidence for a relationship between anakinra treatment and development of serious infection, malignancy, or bone marrow suppression was demonstrated in this study, but longer-term safety studies will be necessary.

In conclusion, this report adds significantly to accumulating data demonstrating that anakinra, self-administered by daily SC injection in patients with active RA, is both safe and effective in controlling the signs and symptoms of inflammation. The results add to the data suggesting that anakinra will be a useful addition to the armamentarium for managing patients with active RA (16, 24, 30).

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A:

The authors thank Dr. Edmund Ng for assistance with statistical analyses and recognize the work of the European Group of Clinical Investigators.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A:
  • 1
    Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor α in rheumatoid arthritis. Arthritis Rheum 1995; 38: 15160.
  • 2
    Dinarello CA. The role of the interleukin-1 receptor antagonist in blocking inflammation mediated by interleukin-1. N Engl J Med 2000; 343: 7324.
  • 3
    Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 158693.
  • 4
    Brennan FM, Maini RN, Feldmann M. TNF alpha: a pivotal role in rheumatoid arthritis? Br J Rheumatol 1992; 31: 2938.
  • 5
    Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996; 87: 2095147.
  • 6
    Lipsky PE, van der Heijde DMFM, St Clair WE, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis: Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000; 343: 1594602.
  • 7
    Van den Berg WB. Lessons for joint destruction from animal models. Curr Opin Rheumatol 1997; 9: 2218.
  • 8
    Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 1990; 33: 30515.
  • 9
    Seckinger P, Dayer JM. Natural inhibitors of TNF. In: AggarwalBB, VilcekJ, editors. Tumor necrosis factor: structure, function, and mechanism of action. New York: Marcel Dekker; 1992. p. 21738.
  • 10
    Rankin EC, Choy EH, Kassimos D, Kingsley GH, Sopwith AM, Isenberg DA, et al. The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. Br J Rheumatol 1995; 34: 33442.
  • 11
    Moreland LW, Heck LW Jr, Koopman WJ. Biologic agents for treating rheumatoid arthritis: concepts and progress. Arthritis Rheum 1997; 40: 397409.
  • 12
    Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997; 337: 1417.
  • 13
    Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 1993; 36: 168190.
  • 14
    Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344: 110510.
  • 15
    Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M. Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: the IL-1Ra Arthritis Study Group. Arthritis Rheum 1996; 39: 1092101.
  • 16
    Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998; 41: 2196204.
  • 17
    Dinarello CA. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int Rev Immunol 1998; 16: 45799.
  • 18
    Firestein GS, Boyle DL, Yu C, Paine MM, Whisenand TD, Zvaifler NJ, et al. Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum 1994; 37: 64452.
  • 19
    Arend WP. Interleukin 1 receptor antagonist: a new member of the interleukin 1 family. J Clin Invest 1991; 88: 144551.
  • 20
    Lebsack ME, Paul CC, Bloedow DC, Burch FX, Sack MA, Chase W, et al. Subcutaneous IL-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 1991; 34 Suppl 9: S45.
  • 21
    Bendele A, McAbee T, Sennello G, Frazier J, Chlipala E, McCabe D. Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis: comparison of efficacy in animal models with human clinical data. Arthritis Rheum 1999; 42: 498506.
  • 22
    Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 72735.
  • 23
    Paulus HE, Egger MJ, Ward JR, Williams HJ, and the Cooperative Systematic Studies of the Rheumatic Diseases Group. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum 1990; 33: 47784.
  • 24
    Jiang Y, Genant H, Watt I, Cobby M, Bresnihan B, Aitchison R, et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 2000; 43: 10019.
  • 25
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
  • 26
    Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980; 23: 13745.
  • 27
    Genant KH, Jiang Y, Peterfy C, Lu Y, Redei J, Countryman PJ. Assessment of rheumatoid arthritis using a modified scoring method on digitized and original radiographs. Arthritis Rheum 1998; 41: 158390.
  • 28
    Larsen A, Dale K, Eck M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn 1977; 8: 48191.
  • 29
    Wells GA, Tugwell P, Kraag GR, Baker PR, Groh J, Redelmeier DA. Minimum important difference between patients with rheumatoid arthritis: the patient's perspective. J Rheumatol 1993; 20: 55760.
  • 30
    Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 61424.

APPENDIX A:

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX A:

THE EUROPEAN GROUP OF CLINICAL INVESTIGATORS

G. Nuki (Edinburgh, UK), B. Bresnihan (Dublin, Ireland), R. M. Bernstein (Manchester, UK), E. George (Merseyside, UK), P. Sheldon (Leicester, UK), M. Doherty (Nottingham, UK), P. Emery (Birmingham, UK), B. Hazleman (Cambridge, UK), P. J. Maddison (Bath, UK), D. G. I. Scott (Norwich, Norfolk, UK), M. Snaith (Sheffield, UK), B. Williams (Cardiff, UK), A. J. Taggart (Belfast, UK), M. G. Molloy (Cork, Ireland), J. Feely (Dublin, Ireland), R. Gustafsson (Stockholm, Sweden), H. Locht (Linkoping, Sweden), R. Manthorpe (Malmo, Sweden), F. Wollheim (Lund, Sweden), S. C. Breedveld (Leiden, The Netherlands), L. van de Putte (Nijmegen, The Netherlands), J. W. J. Bijlsma (Utrecht, The Netherlands), P. D. Botzenhardt (Bremen, Germany), D. J. Kalden (Erlangen, Germany), D. Burmester (Berlin, Germany), J. P. Kaltwasser (Frankfurt, Germany), J. S. Smolen (Vienna, Austria), J. Broll (Vienna, Austria), R. Rau (Ratingen, Germany), B. Rozman (Ljubljana, Slovenia), S. Bombardieri (Pisa, Italy), S. Todesco (Padova, Italy), J. M. Alvaro–Gracia (Madrid, Spain), E. Batlle-Gaulda (Alicante, Spain), Z. Domljan (Zagreb, Croatia), K. Pavelka (Prague, Czech Republic).