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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Objective

We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study.

Methods

This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6–17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect ≥21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008.

Results

Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient.

Conclusion

Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

Juvenile idiopathic arthritis (JIA) (1) is the most common chronic pediatric rheumatic disease, affecting up to 294,000 children in the US alone and 4 of every 1,000 children worldwide (2). The disability and pain associated with JIA negatively impact a patient's physical and psychological health; additionally, JIA is associated with a significant burden for caregivers (3–5).

JIA is typically treated with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX), sulfasalazine, and leflunomide, or with biologic agents (6–13). However, not all patients respond to these treatments, and some DMARDs or antiinflammatory agents are associated with toxicities that limit long-term use or diminish compliance (14–17). Thus, there is a need for durable and well-tolerated long-term treatment options for patients with JIA.

Abatacept, a soluble fusion protein consisting of the extracellular domain of human CTLA-4 linked to a modified Fc portion of human IgG1, is the first in a class of agents that selectively modulates the CD80/CD86:CD28 costimulatory signal required for full T cell activation, making its mechanism of action fundamentally different from that of biologic agents that target tumor necrosis factor α (TNFα) or other cytokines. The efficacy and safety of abatacept have been demonstrated in adult patients with rheumatoid arthritis (RA) who experienced an inadequate response to MTX and anti-TNF biologics (18, 19) as well as in MTX-naive patients (20). Long-term data from adults demonstrate the sustained or improved efficacy of abatacept over time (21–23).

We previously reported the safety, tolerability, and efficacy of abatacept in children and adolescents with JIA who demonstrated an inadequate response or intolerance to at least 1 DMARD (24). During the first 2 phases of the study, 122 patients who were responders (according to the American College of Rheumatology [ACR] Pediatric 30 [Pedi 30] criteria for improvement) (25) at the end of a 4-month, open-label lead-in phase were subsequently randomized in a double-blind manner to receive either abatacept or placebo for 6 months or until they experienced a disease flare. During this double-blind withdrawal phase, placebo-treated patients were 3 times as likely to experience a flare compared with patients who continued to be treated with abatacept. Forty percent of abatacept-treated patients achieved an ACR Pedi 90 response at the end of the double-blind phase, compared with 16% of placebo-treated patients.

The purpose of this open-label extension was to assess the long-term safety and efficacy of abatacept in 3 groups of patients with JIA: 1) those who were treated continuously with abatacept during the open-label lead-in phase, the double-blind phase, and the open-label extension, 2) those who were randomized to receive placebo during the double-blind withdrawal phase and reinitiated treatment with abatacept during the open-label extension, and 3) those who did not achieve an ACR Pedi 30 response at the end of the open-label lead-in phase and thus did not qualify for randomization but continued treatment with abatacept during the open-label extension.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Patients and study design.

The study methodology has been previously described (24). Briefly, this was a phase III, double-blind, randomized, controlled, withdrawal trial in patients with JIA ages 6–17 years from 43 Paediatric Rheumatology International Trials Organization/Pediatric Rheumatology Collaborative Study Group pediatric rheumatology centers in Europe, Latin America, and the US (26). To be eligible, patients were required to have a history of at least 5 joints with active arthritis (swollen joints or joints with limited range of motion and pain or tenderness) and active disease at the time of enrollment (≥2 joints with active arthritis and 2 joints with limited range of motion). Additionally, patients were required to have had an inadequate response or intolerance to at least 1 DMARD, including TNF-blocking agents. Patients were excluded if they had active uveitis, major concurrent medical conditions, or were pregnant or lactating. All patients were asked to practice effective contraception. Live vaccines were prohibited within 3 months before the first dose of study medication and throughout the study. All patients were evaluated for tuberculosis with a purified protein derivative (PPD) test during screening. Those with a positive PPD test result at the time of screening were not eligible for the study if they had evidence of active tuberculosis. Patients who had an isolated positive PPD test result were allowed to enter the study if they had completed at least 4 weeks of therapy for latent tuberculosis and had negative results of chest radiography at the time of enrollment.

The study consisted of 3 phases: an open-label lead-in phase, a double-blind withdrawal phase (24), and an open-label extension; the third phase is the subject of the current report. During the open-label lead-in phase, patients were treated with abatacept (10 mg/kg at each visit, up to a maximum dose of 1,000 mg) by 30-minute intravenous infusion on days 1, 15, 29, 57, and 85. On day 113, all patients satisfying the ACR Pedi 30 threshold of response qualified for randomization (1:1) in the double-blind withdrawal phase to receive abatacept (10 mg/kg) or placebo for 6 months or until an arthritis flare. Patients eligible to enter the open-label long-term extension (LTE) phase were those who completed the double-blind phase without experiencing an arthritis flare, discontinued participation in the double-blind phase due to an arthritis flare, or completed the open-label lead-in phase without achieving an ACR Pedi 30 response and therefore did not qualify for randomization.

Treatment.

All patients in the open-label LTE were treated with 10 mg/kg abatacept, up to a maximum dose of 1,000 mg for those weighing ≥100 kg. Patients received 30-minute infusions every 28 days, and the efficacy and safety of abatacept were assessed at each visit. The dosages of oral steroids (maximum 10 mg/day prednisone equivalent or 0.2 mg/kg/day, whichever was less) and MTX (≤30 mg/m2 body surface area/week up to an absolute maximum of 40 mg/m2/week) could be adjusted during the open-label LTE. The use of nonsteroidal antiinflammatory drugs or analgesics was permitted in patients experiencing pain that was not adequately controlled by the baseline and study medications. The addition of hydroxychloroquine, sulfasalazine, or azathioprine was permitted during the open-label LTE, but no other DMARDs were allowed during the study. Up to 2 intraarticular injections of corticosteroids per year were permitted; any injected joint was considered “active” at all subsequent visits, regardless of the actual clinical status of that joint.

Outcomes.

We assessed the following 6 core ACR Pedi response variables (27): 1) the number of joints with active disease, 2) the number of joints with limited range of motion, 3) physician's global assessment of disease severity, on a 100-mm visual analog scale (VAS), 4) parents' global assessment of the patient's overall well-being, on a 100-mm VAS, 5) functional ability, using the validated translated version of the Childhood Health Assessment Questionnaire (C-HAQ) (28, 29) disability index (0–3-point scale), and 6) the erythrocyte sedimentation rate (30). Efficacy end points included improvement in clinical status from baseline as measured by ACR Pedi responses (11). Using these assessments, improvement was primarily defined by an ACR Pedi 30 response, as follows: an improvement of ≥30% in at least 3 of 6 core variables, with no more than 1 of the remaining variables worsened by ≥30% (26). ACR Pedi 50, Pedi 70, Pedi 90, and Pedi 100 response rates were generated in a similar manner. The proportion of patients with “inactive disease” (defined as having no joint with active disease, a physician's global assessment of disease severity score <10 mm, and an ESR ≤20 mm/hour) was also assessed (31).

The primary safety end points included the number and proportion of patients experiencing adverse events (AEs) and serious adverse events (SAEs). Physical examinations were performed, and measurements of vital signs were recorded at each visit. Patients were assessed for the presence of anti-abatacept antibodies in their sera. Marked abnormalities of laboratory assessments were noted at each visit.

Statistical analysis.

Efficacy and safety analyses were based on data derived from all patients who entered the open-label LTE phase (153 of 190 [80.5%]) and received at least 1 infusion of study medication. Data from all patients treated with abatacept during the open-label LTE phase were pooled for safety analyses. Efficacy analyses were performed for the following 3 subgroups: 1) patients continuously treated with abatacept during the open-label lead-in, the double-blind withdrawal phase, and the open-label LTE phase (DB abatacept group), 2) patients who were randomized to receive placebo during the double-blind phase and were reinitiated to treatment with abatacept during the open-label LTE (DB placebo group), and 3) patients who did not achieve an ACR Pedi 30 response during the open-label lead-in phase and thus did not qualify for randomization but continued treatment with abatacept during the open-label LTE (i.e., those who did not initially achieve at least an ACR Pedi 30 response). Each of these populations was also subjected to post hoc analysis based on prior exposure to biologic therapy. All efficacy analyses were based on patients for whom data were available at the designated time point.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Patient disposition and baseline characteristics.

One hundred ninety patients were entered into the study, and 170 (89.5%) completed the original 4-month open-label lead-in phase (Figure 1). Of these 170 patients, 123 (72%) achieved an ACR Pedi 30 response and were eligible for randomization; the 47 patients who did not achieve an ACR Pedi 30 response (nonresponders) were ineligible for randomization. All but 1 of these 123 patients were randomized and treated with either abatacept 10 mg/kg (n = 60) or placebo (n = 62) in the double-blind randomized withdrawal phase (24).

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Figure 1. Disposition of the juvenile rheumatoid arthritis patients enrolled in the study. The diagram reflects all available information through May 7, 2008.

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One hundred fifty-three (90%) of the 170 patients completing the open-label lead-in phase entered the open-label LTE. These 153 patients included 117 (58 of 60 patients in the DB abatacept group and 59 of 62 patients in the DB placebo group) of the 122 patients from the double-blind phase and 36 of the 47 patients who were not randomized after the open-label lead-in phase due to an inadequate response at the time. Forty-two patients who entered the open-label LTE discontinued treatment (10 patients from the DB abatacept group, 16 from the DB placebo group, and 16 patients from the group of nonresponders). Twenty of these 42 patients discontinued due to lack of efficacy, and 55% of these patients (11 of 20) were from the group of nonresponders. Three of the 42 patients discontinued treatment due to AEs, and the remainder were lost to followup or discontinued for other reasons.

One hundred forty (74%) of the original 190 patients were concomitantly treated with MTX (mean dosage 13.2 mg/m2/week) (Table 1). A similar proportion of patients who entered the open-label LTE were concomitantly treated with MTX (mean dosage 12.9 mg/m2/week).

Table 1. Demographics and clinical characteristics of the JIA patients at the beginning of the open-label lead-in phase*
CharacteristicPatients entering open-label extensionOverall study population (n = 190)
Less than an ACR Pedi 30 response initially (n = 36)Double-blind abatacept (n = 58)Double-blind placebo (n = 59)Total (n = 153)
  • *

    Except where indicated otherwise, values are the mean ± SD. JIA = juvenile idiopathic arthritis; ACR Pedi 30 = American College of Rheumatology Pediatric 30 criteria for improvement; C-HAQ = Childhood Health Assessment Questionnaire (scale 0–3); VAS = visual analog scale; RF = rheumatoid factor; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; MTX = methotrexate.

Age, years12.7 ± 3.112.4 ± 2.912.0 ± 2.912.3 ± 2.912.4 ± 3.0
Female sex, no. (%)23 (63.9)41 (70.7)42 (71.2)106 (69.3)137 (72.1)
Duration of JIA, years4.8 ± 3.93.8 ± 3.84.0 ± 3.54.1 ± 3.74.4 ± 3.8
No. of joints with active arthritis14.9 ± 13.617.8 ± 11.214.9 ± 13.016.0 ± 12.516.2 ± 12.7
No. of joints with limited range of motion17.1 ± 18.016.7 ± 12.214.6 ± 13.916.0 ± 14.316.3 ± 14.5
C-HAQ disability index score, 0–3 scale1.1 ± 0.91.3 ± 0.71.3 ± 0.81.2 ± 0.81.3 ± 0.8
Parent's assessment of overall well-being     
 100-mm VAS44.2 ± 25.141.8 ± 22.940.4 ± 25.141.8 ± 24.144.5 ± 24.6
 Range4–950–921–950–950–100
Physician's global assessment of disease activity     
 100-mm VAS51.41 ± 22.452.9 ± 17.851.7 ± 20.852.1 ± 20.054.2 ± 20.3
 Range10–10018–9910–9810–10010–100
JIA subtype, no. (%)     
 Oligoarthritis, extended3 (8.3)9 (15.5)6 (10.2)18 (11.8)27 (14)
 RF+ polyarthritis8 (22.2)13 (22.4)12 (20.3)33 (21.6)38 (20)
 RF− polyarthritis16 (44.4)25 (43.1)26 (44.1)67 (43.8)84 (44)
 Systemic arthritis9 (25.0)11 (19.0)12 (20.3)32 (20.9)37 (20)
ESR, mm/hour30.6 ± 21.931.3 ± 27.231.5 ± 27.731.2 ± 26.132 ± 26.8
CRP, mg/dl (normal ≤4.9)3.9 ± 4.93.0 ± 4.62.8 ± 3.53.1 ± 4.33.2 ± 4.4
MTX dosage, mg/m2 week     
 Patients, no. (%)26 (72)48 (83)46 (78)120 (78)140 (74)
 Dosage13.2 ± 4.913.1 ± 4.912.5 ± 4.712.9 ± 4.813.2 ± 4.7

Fifty-seven (30%) of the original 190 patients had prior exposure to biologic therapy; of these, 32 (56.1% [7 patients in the DB abatacept group, 13 patients in the DB placebo group, and 12 nonresponders) entered the open-label LTE, and 21 remained through day 589. Thus, 11 of the 42 patients who discontinued treatment during the open-label LTE had prior exposure to biologic therapy.

The baseline demographics and disease characteristics at study entry (open-label lead-in phase) of patients entering the open-label LTE were similar to those reported for the full study population (Table 1). Sixty-nine percent of these 153 patients were female, and the mean disease duration was 4.1 years. These patients had an average of 16.0 joints with active disease and had significant disability (mean C-HAQ disability index score = 1.2). The most common JIA subtype was RF-negative polyarthritis. One hundred twenty (78%) of the 153 patients entering the open-label LTE were receiving concomitant MTX at baseline, at a mean dosage of 12.9 mg/m2/week.

All patients had received treatment for at least 21 months at the time of database lock; the patients who were recruited earliest to participate in the study had been treated longer (the maximum duration of therapy was 52 months at the time of database lock). Patients treated continuously with abatacept through the first 2 phases of the study received abatacept for 10 months prior to the open-label LTE and therefore received continuous therapy for a minimum of 31 months, while patients who were not randomized and those treated with placebo during the double-blind phase usually received abatacept for a shorter period of time. The median duration of abatacept treatment among all patients was 1,069 days (range 168–1,457 days); most patients (59.5%) had been treated with abatacept for at least 36 months.

Efficacy of continuous abatacept treatment.

Among the 51 patients for whom data were available on day 589 and who received abatacept continuously during both the double-blind phase and the open-label LTE, 90% (n = 46) had achieved an ACR Pedi 30 response, 88% (n = 45) had achieved an ACR Pedi 50 response, 75% (n = 38) had achieved an ACR Pedi 70 response, 57% (n = 29) had achieved an ACR Pedi 90 response, and 39% (n = 20) had achieved an ACR Pedi 100 response by day 589. Forty-three percent of these patients (n = 22) had achieved “inactive disease” status (Figure 2). Responses were generally maintained or progressively improved during the open-label LTE (Figure 3A). Response was also apparent when measured by the proportion of patients achieving a score of 0 for individual disease activity measures (Table 2).

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Figure 2. Proportions of patients meeting the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement and the proportions achieving an inactive disease status, as assessed on open-label extension day 589 (as-observed analysis). ACR Pedi response rates were calculated for those patients who completed day 589 of abatacept treatment during the open-label extension. Patients in the double-blind (DB) abatacept group were treated continuously with abatacept during the open-label lead-in phase, the double-blind phase, and the open-label extension. Patients in the double-blind placebo group were randomized to receive placebo during the double-blind phase and reinitiated treatment with abatacept during the open-label extension. Initial nonresponders did not achieve an ACR Pedi 30 response during the open-label lead-in and therefore did not qualify for randomization but were treated with abatacept during the open-label extension.

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thumbnail image

Figure 3. American College of Rheumatology (ACR) Pediatric 30 (ACR Pedi 30), ACR Pedi 50, ACR Pedi 70, ACR Pedi 90, and ACR Pedi 100 responses over time. ACR Pedi response rates were calculated for patients who were treated continuously with abatacept during the open-label lead-in phase, the double-blind (DB) phase, and the open-label extension (A), patients who had switched to placebo during the double-blind phase and had treatment with abatacept reinitiated during the open-label extension (B), and patients who did not achieve an ACR Pedi 30 response during the open-label lead-in and therefore were not randomized but were treated with abatacept during the open-label extension (C).

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Table 2. Percentages of patients with scores of 0 for disease activity measures or with a CRP value within the normal range at baseline of the study and by day 589 of the open-label extension*
 Less than an ACR Pedi 30 response initiallyDouble-blind abataceptDouble-blind placebo
Baseline (n = 36)Day 589 (n = 22)Baseline (n = 58)Day 589 (n = 51)Baseline (n = 59)Day 589 (n = 47)
  • *

    CRP = C-reactive protein; ACR Pedi 30 = American College of Rheumatology Pediatric 30 criteria; ROM = range of motion; C-HAQ = Childhood Health Assessment Questionnaire.

  • Fifty patients were assessed.

  • Forty-five patients were assessed.

No. of joints with active arthritis032063043
No. of joints with limited ROM and pain/tenderness664578566
No. of joints with limited ROM027341030
Score of 0 on physician's global assessment of disease018041030
Score of 0 on parent's assessment of overall well-being00226016
Pain score of 000228213
C-HAQ score of 0623245324
CRP level in normal range (0–4.9 mg/dl)699681927696

When an analysis was conducted according to whether these patients had prior exposure to biologic agents, 89%, 87%, 76%, 57%, and 39% of the 46 patients without such experience and who received abatacept during both the double-blind phase and the open-label LTE phase achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses by day 589, respectively. Forty-six percent of these patients achieved inactive disease status. Among 5 patients who had prior exposure to biologic agents and who received abatacept during both the double-blind phase and the open-label LTE, 100%, 100%, 60%, 60%, and 40% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses by day 589, respectively. Twenty percent of these patients achieved inactive disease status.

Efficacy of interrupted abatacept treatment.

Patients who were randomized to receive placebo during the double-blind phase and were then treated with abatacept during the open-label LTE phase (DB placebo group) (Figure 2) achieved clinical responses similar to those achieved by patients treated continuously with abatacept. By day 589, 87% of these 47 patients (n = 41) had achieved an ACR Pedi 30 response, 83% (n = 39) had achieved a Pedi 50 response, 75% (n = 35) had achieved a Pedi 70 response, 40% (n = 19) had achieved a Pedi 90 response, and 19% (n = 9) had achieved a Pedi 100 response. Twenty-three percent of these patients (n = 11) achieved inactive disease status. After reintroduction of abatacept, the response rates increased during the open-label LTE (Figure 3B). As with those patients who received continuous treatment with abatacept, those who were treated with placebo during the double-blind phase and with abatacept during the open-label LTE exhibited significant improvements in disease activity measures (Table 2).

When an analysis was conducted according to whether these patients had prior exposure to biologic agents, 90%, 88%, 81%, 46%, and 22% of 41 patients without such exposure and who were randomized to receive placebo during the double-blind phase and reinitiated abatacept treatment during the open-label LTE phase achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses by day 589, respectively. Twenty-four percent of these patients achieved inactive disease status. Among 6 patients who had prior exposure to biologic agents and who were randomized to receive placebo during the double-blind phase and reinitiated treatment with abatacept during the open-label LTE phase, 67%, 50%, 33%, 0%, and 0% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses by day 589, respectively. One of these patients achieved inactive disease status.

Efficacy in patients not achieving an ACR Pedi 30 response at the end of the open-label lead-in.

Clinically meaningful improvements in disease control were realized with longer exposure to abatacept in patients who did not achieve an ACR Pedi 30 response during the 4-month open-label lead-in period (nonresponders) (Figure 2). Many of these patients exhibited clinically meaningful responses by day 253 of the open-label LTE (57%, 50%, 36%, 7%, and 7% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively) (Figure 3C). By day 589, 73% of these 22 patients (n = 16), 64% (n = 14), 46% (n = 10), 18% (n = 4), and 5% (n = 1) had achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively. One patient achieved inactive disease status during the extension phase. By day 589, nearly one-third of these patients had no joints with active arthritis, and almost two-thirds had no joints with limited range of motion and pain/tenderness (Table 2).

When an analysis was conducted according to whether these patients had prior exposure to biologic agents, 71%, 65%, 53%, 24%, and 6% of 17 patients without such exposure and who did not achieve an ACR Pedi 30 response after the initial open-label lead-in phase exhibited ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses by day 589, respectively. Six percent of these patients achieved inactive disease status. Among 5 patients who had prior exposure to biologic agents and who did not achieve an ACR Pedi 30 response during the 4-month open-label lead-in period, 80%, 60%, and 20% achieved ACR Pedi 30, Pedi 50, and Pedi 70 responses by day 589, respectively. No patients in this group achieved an ACR Pedi 90 or ACR Pedi 100 response or inactive disease status.

Safety.

The favorable safety profile previously reported (24) continued in the open-label LTE, as treatment with abatacept continued to be generally safe and well tolerated. The most common AEs during open-label treatment included nasopharyngitis (n = 27), upper respiratory tract infection (n = 25), vomiting (n = 23), and pyrexia (n = 22) (Table 3).

Table 3. Most common AEs and SAEs during the open-label extension*
 Less than an ACR Pedi 30 response initially (n = 36)Double-blind abatacept (n = 58)Double-blind placebo (n = 59)Total (n = 153)
  • *

    Values are the number (%). Most common adverse events (AEs) and most common serious adverse events (SAEs) were defined as those occurring in ≥10% and ≥1% of the total group, respectively. ACR Pedi 30 = American College of Rheumatology Pediatric 30 criteria; URI = upper respiratory tract infection.

  • All related to underlying disease.

Most common AEs    
 Nasopharyngitis6 (16.7)14 (24.1)7 (11.9)27 (17.6)
 URI11 (30.6)6 (10.3)8 (13.6)25 (16.3)
 Vomiting5 (13.9)9 (15.5)9 (15.3)23 (15.0)
 Pyrexia7 (19.4)7 (12.1)8 (13.6)22 (14.4)
 Diarrhea6 (16.7)5 (8.6)9 (15.3)20 (13.1)
 Pharyngitis2 (5.6)8 (13.8)9 (15.3)19 (12.4)
 Cough5 (13.9)7 (12.1)7 (11.9)19 (12.4)
 Nausea4 (11.1)5 (8.6)8 (13.6)17 (11.1)
Most common SAEs    
 Arthritis disease flare3 (8.3)3 (5.2)06 (3.9)
 Arthralgia1 (2.8)01 (1.7)2 (1.3)
 Foot deformity01 (1.7)1 (1.7)2 (1.3)
 Pyrexia01 (1.7)1 (1.7)2 (1.3)
 Vomiting01 (1.7)1 (1.7)2 (1.3)

During the open-label LTE, 23 patients reported SAEs including an arthritis flare (n = 6), arthralgia (n = 2), foot deformity (n = 2), pyrexia (n = 2), and vomiting (n = 2); arthritis, arthralgia, and foot deformity were assessed by the treating physician as being related to JIA in these patients. The numbers of patients reporting SAEs in the 3 groups were similar (7 patients in the group of nonresponders (19%), 8 patients in the DB abatacept group (14%), and 8 patients in the DB placebo group (14%); arthritis occurred in 3 of the patients who were nonresponders (8%), and in 3 patients in the DB abatacept group (5%).

Five patients experienced acute infusion reactions; the most common of these reactions were dizziness (n = 4), nausea (n = 3), vomiting (n = 2), headache (n = 2), infusion-related reaction (n = 2), hypersensitivity (n = 2), and rhinitis (n = 2). These events were typically single occurrences, with subsequent infusions being well tolerated and not requiring premedication; only 1 patient discontinued participation due to an infusion-related reaction.

Five patients experienced 6 serious infections during the open-label LTE (1 each of dengue fever, erysipelas, gastroenteritis, herpes zoster, bacterial meningitis, and pyelonephritis). There were no reports of tuberculosis during the open-label LTE. One case of uveitis was reported, which resolved subsequent to treatment with topical prednisone; the patient did not discontinue treatment with abatacept. Four benign neoplasms were reported during the open-label LTE (3 skin papillomas and 1 breast fibroadenoma). No malignancies were reported.

Multiple sclerosis (MS) developed in 1 patient, a 12-year-old boy. He had been started on MTX (10.5 mg/m2/week) prior to study initiation and had not previously been treated with another biologic agent for JIA. This patient, who had received placebo during the double-blind phase, presented on day 593 of the open-label LTE with a temporal lobe seizure, and temporal lobe epilepsy was diagnosed. The epilepsy diagnosis was confirmed by electroencephalography, and the patient was discontinued from the study on day 599. The diagnosis of MS was supported by the results of brain magnetic resonance imaging (MRI) on day 631, revealing multiple apparent demyelinated plaques and a subsequent cerebrospinal fluid analysis revealing oligoclonal IgG. The result of MRI performed ∼1 year after the initial event was unchanged. The patient was seropositive for anti–CTLA-4 antibodies on day 85 of the double-blind phase but not at any subsequent visits.

Anti-abatacept and anti–CTLA-4 antibody production.

Seventeen (11%) of the 149 patients for whom samples were available were seropositive for anti-abatacept or anti–CTLA-4 antibodies at some point during the open-label LTE. Nine of the 17 patients had positive results only once, and seropositivity occurred in a similar number of patients in each of the 3 groups. The presence of anti-abatacept or anti–CTLA-4 antibodies did not correlate with changes in abatacept pharmacokinetics, infusion reactions, AEs, SAEs, or loss of efficacy. Over the course of the 3 study phases, 44 (23%) of 189 patients were seropositive at least once for anti-abatacept or anti–CTLA-4 antibodies; 26 of the 44 patients were positive only once. Seropositivity occurred in a similar number of patients in each of the 3 groups. In no case did seropositivity correlate with a clinical finding such as an AE, infusion reaction, or change in efficacy.

Data regarding the presence of antinuclear antibodies (ANAs) or anti–double-stranded DNA (anti-dsDNA) antibodies were available for patients who discontinued treatment during the double-blind withdrawal phase and entered the open-label LTE phase. Three of the 20 patients who had no measurable ANAs at the original baseline seroconverted during the open-label LTE. Two of the 5 patients who initially had an elevated ANA level seroreverted during the open-label LTE. Only 1 of the 20 patients who had negative results of an anti-dsDNA antibody test at the original baseline seroconverted during the open-label LTE. Six patients who initially tested positive for anti-dsDNA antibodies seroreverted during the LTE.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

The open-label LTE phase of this study showed that the clinical benefit of abatacept treatment was maintained or progressively improved with time, and that abatacept was safe and well tolerated in patients with JIA in all 3 of the treatment cohorts studied. Clinically meaningful responses were attained by most patients for whom data were available, some of whom achieved an ACR Pedi 90 or ACR Pedi 100 response or inactive disease status that was maintained over time. Protocol-defined or unplanned interruptions in therapy were well tolerated and were not associated with AEs or infusion-related reactions upon reintroduction of therapy. Responses in this group “caught up” with those in the group receiving continuous abatacept therapy.

The design of this study is generally similar to that of trials conducted with etanercept, adalimumab, and tocilizumab in JIA (6, 9, 11), some of which have provided long-term data (32, 33). However, there are important differences in the patient populations in these studies. Thirty percent of the patients (57 of 190) entering the current study had previously been treated unsuccessfully with at least 1 anti-TNF agent. Other studies included a different proportion of JIA subtypes or focused on systemic-onset JIA, and few studies followed up patients who did not initially experience a response to treatment during the long-term extensions.

In the current open-label LTE, a majority of patients completing the extension phase achieved significant relief from JIA symptoms and signs. In the open-label LTE of the etanercept study, ∼75–80% of patients treated continuously with etanercept achieved at least an ACR Pedi 70 response after 3–4 years, with 11 of 11 patients achieving an ACR Pedi 70 response by year 8 (32). Among a small subset of patients in the open-label LTE phase of the study of adalimumab in JIA, ∼80% achieved at least an ACR Pedi 70 response (33). Twenty percent of patients in the current trial were classified as having systemic-onset JIA but had no active systemic signs/symptoms at the time of enrollment. By day 589, the ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and inactive disease response rates in patients with systemic-onset JIA treated with abatacept were 88%, 88%, 63%, 13%, and 25%, respectively, in the DB abatacept group; 91%, 91%, 73%, 36%, and 46%, respectively, in the DB placebo group; and 57%, 29%, 29%, 0%, and 0%, respectively, in the group of patients who did not achieve an ACR Pedi 30 response after the initial 4-month open-label phase of treatment.

A distinguishing feature of the current study is the treatment and long-term followup of patients who did not achieve an ACR Pedi 30 response at the end of the 4-month open-label lead-in phase and therefore were not eligible for randomization; this duration was chosen based on experience in RA. A majority of patients in whom JIA had not responded to treatment by the end of the initial open-label lead-in phase did experience a response following further treatment during the open-label LTE; 16 (73%) of 22 patients had achieved an ACR Pedi 30 response by day 589, and some patients achieved clinically significant responses (i.e., an ACR Pedi 70 response or better) by day 589. These data are similar to those from the phase III etanercept study, in which 4 (67%) of 6 nonresponders had achieved an ACR Pedi 30 response at 2 years (34), suggesting that some patients require treatment for >3–4 months in order for a response to be achieved. Based on these data, a 4-month period may not be a sufficient therapeutic trial with abatacept for some patients; furthermore, in patients in whom JIA responds to abatacept, the level of response often increases with a longer duration of therapy. The time course of response to abatacept in this trial is validated by data from adult RA trials, in which longer treatment duration was associated with progressive improvement in response (23, 35).

Most patients (58 of 60) treated with abatacept during the double-blind phase continued into the open-label LTE. This 97% retention rate, together with the fact that only 3 of these patients withdrew due to AEs during the open-label phase, suggests that long-term treatment with abatacept is safe and well tolerated, and the rate is supported by long-term retention rates in adult populations (23). No cases of tuberculosis, opportunistic infections, or malignancies were reported during open-label treatment. MS continues to be very rare in the abatacept clinical trial experience; only 1 other case has been reported, in an adult with RA (20). The incidence of serious infection was low, and no type of serious infection occurred in more than 1 patient. The safety profile was generally similar across the 3 groups, suggesting that interrupted treatment or delayed clinical response does not impact safety. The presence of anti-abatacept or anti–CTLA-4 antibodies was not associated with an increased number of AEs or diminished efficacy. Some patients seroconverted to ANA or anti-dsDNA positivity without any associated clinical findings.

There are limitations to the current study design. The analysis was conducted in an as-observed manner. The open-label lead-in phase, which is standard in most JIA trials, minimizes the time spent receiving placebo but biases the analysis toward responders. However, many of the patients who did not initially respond to abatacept experienced clinical benefit upon extended treatment, suggesting that the 4-month open-label lead-in phase was too short to maximize the proportion of patients who experienced a response to abatacept. Additionally, the number of patients and the extent of treatment to date are not sufficient to detect rare safety events; further followup of this cohort and a planned registry will help in detecting such rare events. Last, the trial did not include radiographic assessments, similar to other recent trials in JIA.

The results of the current open-label LTE of a double-blind, randomized study suggest that abatacept is a promising treatment of JIA in children and adolescents. Patients who were continuously treated with abatacept experienced significant improvements in disease symptoms, and interruption of therapy for as long as 6 months was well tolerated. Patients with prior exposure to anti-TNF agents and those who were naive for treatment with biologic agents experienced significant improvements in disease symptoms. The presence of anti-abatacept antibodies was not associated with significant efficacy or safety concerns. The high degree of patient retention helps support the conclusion that abatacept treatment was generally safe and well tolerated. Even among those who did not initially experience a response to abatacept, clinically significant benefits were obtained after longer treatment, with additional improvement over time, suggesting that, in some patients, a 4-month treatment period may not be sufficient to determine how well a patient will respond to abatacept.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Drs. Ruperto, Lovell, Martini, and Giannini had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Ruperto, Lovell, Sigal, Block, Martini, Giannini.

Acquisition of data. Ruperto, Lovell, Quartier, Paz, Rubio-Pérez, Silva, Abud-Mendoza, Burgos-Vargas, Gerloni, Melo-Gomes, Saad-Magalhães, Chavez-Corrales, Huemer, Kivitz, Blanco, Foeldvari, Hofer, Horneff, Huppertz, Job-Deslandre, Loy, Minden, Punaro, Flores Nunez, Sigal, Martini.

Analysis and interpretation of data. Ruperto, Lovell, Sigal, Nys, Martini, Giannini.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

The study, analysis, and manuscript preparation were conceived and driven by the Paediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Publication of this manuscript was not contingent on approval by the study sponsor.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

We thank the following investigators who participated in the trial: Sheila Oliveira, MD, Flavio Sztajnbok, MD, Claudia Schainberg, MD, Morton Scheinberg, MD (Brazil); Brigitte Bader Meunier, MD, Michael Fischbach, MD, Irene Lemelle, MD, Anne Marie Prieur, MD, Richard Mouy, MD (France); Javier Orozco, MD (Mexico); Maria Alessio, MD, Angelo Ravelli, MD, Loredana Lepore, MD, Elisabetta Cortis, MD, Fernanda Falcini, MD (Italy); Immaculada Calvo, MD (Spain); Anne B. Eberhard, MD, Phillip Hashkes, MD, Christine Hom, MD, Larry Jung, MD, Nancy Olson, MD, Carol Wallace, MD (US). We also thank Christine Cooke, Patricia Cornet, Viola Bonness, Tamara Repsher, and Lori Pagliaro, and acknowledge additional support with statistics from Sandra Sinisi and Ye Zhou, Bristol-Myers Squibb. Finally, we thank Brian Atkinson, Bristol-Myers Squibb, for his writing and editorial assistance.

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  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
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