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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

Objective

To assess the safety and tolerability of tocilizumab (TCZ) as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) in patients with moderate to severe rheumatoid arthritis (RA) who had an inadequate response at study entry to their current treatment with biologic agents or DMARDs.

Methods

This 24-week, multicenter, open-label, phase IIIb study conducted in the US enrolled 886 patients. Treatments were allocated to patients based on their current therapy at study entry. Patients receiving monotherapy with biologic agents were assigned to TCZ 8 mg/kg monotherapy. All other patients were randomized to either TCZ 4 mg/kg + DMARDs or TCZ 8 mg/kg + DMARDs. The primary end point was the number and percentage of patients with serious adverse events (SAEs) during 24 weeks of TCZ treatment. Efficacy assessments were evaluated as secondary outcomes. Data were analyzed descriptively.

Results

Overall, 69 patients (7.8%) reported ≥1 SAEs. The rate of SAEs per 100 person-years was 28.3 (95% confidence interval [95% CI] 23.1–34.4) overall and was similar across treatment groups: 29.1 (95% CI 21.0–39.2), 30.3 (95% CI 22.2–40.2), and 20.6 (95% CI 10.3–36.9) in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively. The most common SAEs were infections (i.e., pneumonia [1.0%] and cellulitis [0.9%]). In addition, American College of Rheumatology response rates and reductions in mean Disease Activity Score based on a 28-joint count were generally similar among treatment groups.

Conclusion

The safety findings in this study were consistent with the previously identified safety profile of TCZ. TCZ had an AE profile consistent with prior randomized blinded studies and was effective when administered as either monotherapy or in combination with DMARDs for the treatment of RA.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

Rheumatoid arthritis (RA) has been shown to be associated with an increased risk for comorbidities such as serious infections (SIs), malignancies, and cardiac disease, with additional risks linked to currently prescribed therapies, including disease-modifying antirheumatic drugs (DMARDs) (1, 2). Awareness of therapeutic agent safety issues, appropriate screening, and individualized treatment for patients can help minimize the potential treatment risks.

Tocilizumab (TCZ) is a humanized interleukin-6 (IL-6) receptor monoclonal antibody that competitively inhibits the binding of IL-6 to its receptor (3). The clinical efficacy and safety of TCZ in RA were demonstrated in 5 phase III randomized controlled trials (RCTs) (4–8), and the long-term efficacy and safety of continued TCZ exposure are being evaluated in open-label extension phases (9). Together, these studies have demonstrated that TCZ, alone or in combination with methotrexate (MTX) or other DMARDs, significantly reduces the signs and symptoms of RA compared to DMARDs alone.

Based on this extensive clinical trial program of more than 4,000 patients, a comprehensive safety profile has been established for TCZ; however, findings from randomized clinical trials may not always reflect real-world experience. Therefore, the ACT-STAR study was designed to more closely reflect clinical practice in order to further assess the safety and tolerability of TCZ as monotherapy or in combination with DMARDs in patients with moderate to severe active RA who had an inadequate response to their current therapy at study entry. This study also aimed to implement and assess risk mitigation strategies for adverse events (AEs) of special interest and laboratory abnormalities. Additionally, the ACT-STAR study explored the effect of increasing the TCZ dose from 4 to 8 mg/kg in combination with DMARDs.

Significance & Innovations

  • Tocilizumab (TCZ) treatment demonstrated numerically similar safety and efficacy results whether given as monotherapy or in combination with disease-modifying antirheumatic drugs.

  • Rates of serious adverse events were not elevated in patients who did not have a washout of biologic agents before switching to TCZ.

  • TCZ dose escalations were well tolerated and accompanied by efficacy improvements in some cases.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

Study design.

This randomized, open-label, phase IIIb study was conducted in the US and included a 28-day screening period, a 24-week treatment period, and 12 weeks of followup after the last infusion. The 24-week treatment period occurred between May 2009 and July 2010. The patients satisfying all entry criteria were treated with TCZ as monotherapy or in combination with ≥1 DMARDs, depending on their current therapy at screening. Patients receiving monotherapy with biologic agents at screening were assigned to the TCZ 8 mg/kg monotherapy group, and all other patients (i.e., receiving ≥1 DMARDs with or without biologic DMARDs) were randomized to either the TCZ 4 mg/kg + DMARDs group or the TCZ 8 mg/kg + DMARDs group. There were several key differences between the ACT-STAR study and previous phase III RCT inclusion/exclusion criteria: 1) the ACT-STAR study did not require minimum C-reactive protein (CRP) levels or a minimum erythrocyte sedimentation rate (ESR), while the RCTs required a CRP level ≥1 mg/dl or an ESR ≥28 mm/hour; consequently, the median CRP level at baseline for enrolled patients in the ACT-STAR study was <1 mg/dl; 2) the ACT-STAR study required a tender joint count (TJC) ≥4 and swollen joint count (SJC) ≥4, while the RCTs required a TJC ≥8 and SJC ≥6; and 3) no washout period was required before entry into the ACT-STAR trial for patients previously receiving therapy with biologic agents (a washout period of 6 months was required if the patient received rituximab), while patients entering the RCTs had to discontinue etanercept for ≥2 weeks, infliximab or adalimumab for ≥8 weeks, or anakinra for ≥1 week. Previous exposure to anti-CD20 antibodies or other cell-depleting agents was not allowed in the phase III RCTs.

At week 8, patients in the TCZ 4 mg/kg + DMARDs group who did not achieve at least a 20% improvement from baseline in their TJC and SJC were to have their TCZ dose increased to 8 mg/kg, as specified in the study protocol. Beginning at week 12, patients in the TCZ 4 mg/kg + DMARDs group could have their TCZ dose increased to 8 mg/kg, at the discretion of the investigator. For patients in the TCZ 8 mg/kg + DMARDs group, the TCZ dose could be decreased at any time for safety reasons; however, patients receiving TCZ 8 mg/kg monotherapy could not have their dose reduced. All patients could discontinue TCZ for safety reasons or per the discretion of the physician. DMARD therapy was to be maintained at a stable dose but could also be reduced for safety reasons or per the discretion of the physician.

The study protocol proposed risk mitigation strategies and dose modification guidelines to aid physicians in managing the known and potential risks associated with the clinical use of TCZ. These strategies are related to key events and laboratory abnormalities and recommend TCZ dose reductions or interruptions based on laboratory abnormalities, such as elevations in aspartate aminotransferase (AST) or decreases in neutrophils. The parameters for dose interruption and discontinuation outlined in the study protocol are similar to the dose modification guidelines given in the TCZ prescribing information (10). These guidelines are also in line with previous educational materials provided to health care professionals and patients (see Supplementary Appendix A for the complete list of risk mitigation strategies employed in this study, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.21847/abstract).

This study was conducted in accordance with the principles of the Declaration of Helsinki or with local laws and regulations, whichever afforded greater protection to the individual, and adhered to Good Clinical Practice guidelines. All patients provided written informed consent.

Patients.

Adult patients (ages ≥18 years) with a moderate to severe active RA duration of at least 6 months with ≥4 swollen joints (66-joint count) and ≥4 tender joints (68-joint count) who had an inadequate clinical response to biologic agents or DMARDs or had safety/tolerability issues on stable doses of biologic agents or DMARDs were included. Patients were to continue taking permitted DMARDs (≥1), provided that the dose was stable for at least 7 weeks prior to baseline. Patients were permitted to receive oral corticosteroids, provided the dosage was ≤10 mg/day of prednisone or its equivalent and stable for at least 28 days prior to the study screening. An elevated acute-phase reactant (CRP level or ESR) was not required for study entry.

Standard exclusion criteria were used in this study, including previous treatment with TCZ, any previous treatment with alkylating agents, treatment with intraarticular corticosteroids within 8 weeks prior to screening or intramuscular or intravenous corticosteroids within 12 weeks prior to screening, serum creatinine >1.6 mg/dl in women and >1.9 mg/dl in men, liver enzyme levels (alanine aminotransferase [ALT] or AST) >1.5 times the upper limit of normal (ULN), platelet count <100 × 109/liter, hemoglobin <8.5 gm/dl, white blood cell count <4.0 × 109/liter, absolute neutrophil count <2.0 × 109/liter, absolute lymphocyte count <0.5 × 109/liter, positive hepatitis B or C serologies, total bilirubin greater than the ULN, triglycerides >900 mg/dl at screening (fasted), and other serious general medical conditions.

Assessments.

The study assessments were scheduled at baseline, at every 4 weeks for safety (no laboratory tests at week 20), and at every 8 weeks for efficacy. The primary study end point was the number and percentage of patients with serious AEs (SAEs) during 24 weeks of TCZ monotherapy (8 mg/kg) or TCZ (4 mg/kg or 8 mg/kg) combined with ≥1 DMARDs. Secondary safety end points included the numbers and percentages of patients experiencing AEs of special interest (SIs, anaphylaxis, complications of diverticulitis including lower gastrointestinal [GI] perforations, myocardial infarction/acute coronary syndrome, stroke, serious hepatic events, spontaneous or serious bleeding, demyelination-related events, and malignant neoplasms), AEs and SAEs causing discontinuation of TCZ therapy, and changes in laboratory values related to pharmacodynamic IL-6 inhibition (i.e., neutrophil and platelet decreases and lipid and liver enzyme elevations).

All efficacy end points were considered secondary. Efficacy and quality of life secondary end points included the response rate according to the American College of Rheumatology (ACR) 20% (ACR20), 50% (ACR50), and 70% (ACR70) improvement criteria and the Disease Activity Score based on a 28-joint assessment (DAS28; including change from baseline, achievement of remission [DAS28 score <2.6], and low disease activity [DAS28 score ≤3.2]). Individual parameters of the ACR core data set (TJC, SJC, visual analog scales [100 mm] for pain, patient and investigator global assessments of disease status, patient-assessed disability, and CRP level) were also assessed (11). Additionally, the change from baseline in Routine Assessment of Patient Index Data 3 (RAPID-3) score (12) and the fatigue visual analog scale were evaluated.

Statistical analysis.

Data were analyzed descriptively; there were no formal statistical comparisons among the treatment groups. The confidence interval (CI) approach was used to determine sample size. Pooled data from previous phase III studies showed an SAE incidence rate of 5.7% for all TCZ-treated patients. Based on this assumption and projecting a 10% dropout rate, ∼750 patients were needed to achieve a 2-sided 95% CI width within 3.4%.

Safety data were analyzed using the safety population, defined as all enrolled patients who received at least 1 TCZ dose and who had at least 1 postbaseline safety assessment. Patients were included in the TCZ dose group that corresponded to the first TCZ dose they received and were determined as monotherapy or combination therapy according to whether or not they took ≥1 DMARDs during the observation period. Efficacy and quality of life outcomes were analyzed using the intent-to-treat (ITT) population, defined as all enrolled patients who received at least 1 dose of study medication. Patients in the ITT group were included in the treatment group into which they were randomized or assigned, regardless of the treatment they actually received. Subgroup analyses were performed by stratifying patients according to dose-escalation status (TCZ dose escalated from 4 mg/kg to 8 mg/kg at week 8, after week 8, or not at all), previous inadequate response to therapy (inadequate responders to DMARDs or biologic agents), and timing of biologic agent use (previous biologic agent use [≥2 months prior to enrollment], current biologic agent use [<2 months prior to enrollment], or no prior biologic agent use). The last observation carried forward value was used for missing joint assessments at visits where at least 1 joint was assessed. For the ACR20, ACR50, and ACR70 criteria, patients with missing data were classified as nonresponders. For continuous end points (e.g., DAS28), missing data were treated as missing with no imputation.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

Patient disposition and baseline characteristics.

Of the 886 patients enrolled, 163 were assigned to the TCZ 8 mg/kg monotherapy group. The remaining 723 patients were assigned to combination therapy, with 363 randomized to receive a starting dose of TCZ 4 mg/kg + DMARDs and 360 to receive a starting dose of TCZ 8 mg/kg + DMARDs (3 patients withdrew prior to receiving therapy) (Figure 1). In the initial TCZ 4 mg/kg + DMARDs group, 152 patients (41.9%) were exposed only to TCZ 4 mg/kg + DMARDs, 142 (39.1%) had their dose escalated to TCZ 8 mg/kg + DMARDs at week 8, and 68 (18.7%) had their dose escalated to TCZ 8 mg/kg + DMARDs after week 8. Due to these dose escalations, the TCZ 4 mg/kg + DMARDs group will be referred to as the TCZ 4/8 mg/kg + DMARDs group hereafter. Overall, 82.5% of the patients completed the 24-week study (83.5% of patients in the TCZ 4/8 mg/kg + DMARDs group, 83.9% of patients in the TCZ 8 mg/kg + DMARDs group, and 77.3% of patients in the TCZ 8 mg/kg monotherapy group). For patients who discontinued TCZ, the most common reasons were safety (7.0%), a lack of response (3.4%), or consent withdrawn (2.7%). Eighteen patients discontinued TCZ due to an SAE, most commonly an infection (n = 8). Of the patients who discontinued TCZ due to an AE (n = 60), 13 had an infection, 10 had an abnormal laboratory reading, and 8 experienced a skin disorder.

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Figure 1. Patient disposition (all patients). The flow chart depicts study enrollment, treatment assignment and randomization, and study completion. Patients randomized to the tocilizumab (TCZ) 4 mg/kg + disease-modifying antirheumatic drugs (DMARDs; nonbiologic) group may have withdrawn prior to week 8 while still receiving TCZ 4 mg/kg, or after week 8 while receiving TCZ 4 mg/kg or 8 mg/kg. Additionally, 1 patient randomized to the TCZ 4 mg/kg + DMARDs group and 2 patients randomized to the TCZ 8 mg/kg + DMARDs group withdrew prior to receiving treatment.

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The baseline demographics and clinical characteristics are shown in Table 1. Baseline demographics and disease characteristics were similar among patients receiving TCZ 4/8 mg/kg + DMARDs or TCZ 8 mg/kg + DMARDs. The patients assigned to receive TCZ 8 mg/kg monotherapy had a numerically longer disease duration, higher baseline DAS28 scores, higher TJC and SJC, and a higher likelihood of prior biologic DMARD use due to the protocol specifications that patients assigned to this group had previously used or were currently taking biologic agents.

Table 1. Baseline demographics and clinical characteristics*
 TCZ 4/8 mg/kg + DMARDsTCZ 8 mg/kg + DMARDsTCZ 8 mg/kg monotherapy
  • *

    Values are the mean ± SD unless otherwise indicated. TCZ = tocilizumab; DMARDs = disease-modifying antirheumatic drugs (nonbiologic); TNF = tumor necrosis factor; ITT = intent to treat; DAS28 = Disease Activity Score in 28 joints; CRP = C-reactive protein; SJC = swollen joint count; TJC = tender joint count; VAS = visual analog scale.

  • N = 364 for the TCZ 4/8 mg/kg + DMARDs group, n = 381 for the TCZ 8 mg/kg + DMARDs group, and n = 138 for the TCZ 8 mg/kg monotherapy group. Patients were included in the group that corresponded to the first TCZ dose they received and determined as monotherapy or combination therapy according to if they took ≥1 DMARDs during the observation period. The safety group comprised all patients who received ≥1 TCZ dose and had ≥1 postbaseline safety assessment.

  • N = 362 for the TCZ 4/8 mg/kg + DMARDs group, n = 358 for the TCZ 8 mg/kg + DMARDs group, and n = 163 for the TCZ 8 mg/kg monotherapy group. The ITT population comprised all patients who received ≥1 TCZ dose. Patients were included in the group into which they were randomized or assigned.

  • §

    N = 361.

  • N = 356.

  • #

    N = 357.

Safety population   
 Women, no. (%)273 (75.0)296 (77.7)110 (79.7)
 Age, years55.6 ± 11.954.0 ± 12.153.5 ± 12.6
 Disease duration, years11.5 ± 9.910.5 ± 9.013.5 ± 9.7
 Previous DMARDs, no. (%)   
  None0017 (12.3)
  1188 (51.6)187 (49.1)46 (33.3)
  286 (23.6)102 (26.8)40 (29.0)
  ≥390 (24.7)92 (24.1)35 (25.4)
 Previous biologic agents, no. (%)   
  None126 (34.6)108 (28.3)11 (8.0)
  197 (26.6)95 (24.9)44 (31.9)
  268 (18.7)81 (21.3)41 (29.7)
  ≥373 (20.1)97 (25.5)42 (30.4)
 Past anti-TNF therapy, no. (%)218 (59.9)255 (66.9)120 (87.0)
 Oral steroids, no. (%)183 (50.3)193 (50.7)70 (50.7)
 Background DMARDs1.2 ± 0.391.2 ± 0.450 ± 0.0
 Background DMARDs, no. (%)   
  None1 (0.3)1 (0.3)138 (100)
  1310 (85.2)322 (84.5)0
  250 (13.7)48 (12.6)0
  ≥33 (0.8)10 (2.6)0
ITT population   
 DAS28 score5.66 ± 0.995.54 ± 1.016.01 ± 1.00
 CRP level, mg/dl1.54 ± 2.281.41 ± 2.051.87 ± 3.27
 SJC, 66-joint count17.8 ± 10.618.3 ± 10.720.6 ± 12.0
 TJC, 68-joint count28.1 ± 14.728.2 ± 15.632.6 ± 16.4
 Physician VAS, 100 mm62.3 ± 18.7§63.2 ± 18.165.4 ± 17.5
 Patient VAS, 100 mm62.0 ± 20.658.8 ± 23.068.1 ± 19.6
 Pain VAS, 100 mm56.8 ± 21.054.8 ± 22.9#62.9 ± 19.9

Safety: AEs and SAEs.

The safety results are shown in Table 2. The overall rate of SAEs per 100 person-years was 28.3 (95% CI 23.1–34.4) and was similar among the treatment groups. The most common SAEs were pneumonia (1.0%) and cellulitis (0.9%), with 3.6% of patients reporting ≥1 SIs. The overall rate of SIs per 100 person-years was 11.2 (95% CI 8.0–15.3) and was also similar for each treatment group. Table 2 also summarizes the safety outcomes for patients in the TCZ 4/8 mg/kg + DMARDs group stratified by an increase to TCZ 8 mg/kg + DMARDs at or after week 8. Although the patient-years of exposure in this study are limited, the AEs per person-year as well as SAEs and SIs per 100 person-years were similar pre– and post–TCZ dose escalation.

Table 2. Safety overview of AEs, SAEs, and SIs*
 Total TCZ 4/8 mg/kg + DMARDsTCZ 4/8 mg/kg + DMARDs, escalated to TCZ 8 mg/kg at or after week 8TCZ 4/8 mg/kg + DMARDs, only exposed to TCZ 4 mg/kg§TCZ 8 mg/kg + DMARDsTCZ 8 mg/kg monotherapy#
PreescalationPostescalation
  • *

    Values are the number (percentage) unless otherwise indicated. AEs = adverse events; SAEs = serious AEs; SIs = serious infections; TCZ = tocilizumab; DMARDs = disease-modifying antirheumatic drugs (nonbiologic); PY = person-year; 95% CI = 95% confidence interval.

  • N = 364, 147.9 PYs.

  • N = 210, preescalation 38.5 PYs, and postescalation 51.9 PYs. One patient who was randomized to the TCZ 8 mg/kg + DMARDs group incorrectly received TCZ 4 mg/kg at baseline and was included in the TCZ 4 mg/kg + DMARDs group according to the protocol-specified definition of the safety population. This patient was switched back to the assigned 8 mg/kg dose at week 4; therefore, the patient was not counted in the subgroups of patients who switched at or after week 8 or who did not switch.

  • §

    N = 153, 57.0 PYs.

  • N = 381, 155.3 PYs.

  • #

    N = 138, 53.4 PYs.

  • **

    1 cardiac arrest, 1 cerebrovascular accident.

Patients with ≥1 AEs294 (80.8)136 (64.8)126 (60.0)115 (75.2)309 (81.1)114 (82.6)
 AE leading to death**2 (0.5)002 (1.3)00
 AE leading to TCZ withdrawal32 (8.8)4 (1.9)4 (1.9)24 (15.7)19 (5.0)9 (6.5)
 AE leading to TCZ dose modification/interruption85 (23.4)41 (19.5)23 (11.0)24 (15.7)64 (16.8)30 (21.7)
AEs per PY6.737.555.517.267.167.11
Patients with ≥1 SAEs29 (8.0)2 (1.0)9 (4.3)18 (11.8)32 (8.4)8 (5.8)
 SAE leading to TCZ withdrawal11 (3.0)1 (0.5)2 (1.0)8 (5.2)4 (1.0)3 (2.2)
 SAE leading to TCZ dose modification/interruption7 (1.9)1 (0.5)3 (1.4)3 (2.0)11 (2.9)1 (0.7)
SAEs per 100 PYs (95% CI)29.1 (21.0–39.2)5.2 (0.6–18.8)27.0 (14.7–45.2)47.4 (31.2–68.9)30.3 (22.2–40.2)20.6 (10.3–36.9)
Patients with ≥1 SIs13 (3.6)1 (0.5)3 (1.4)9 (5.9)15 (3.9)4 (2.9)
SIs per 100 PYs (95% CI)10.1 (5.7–16.7)2.6 (0.1–14.5)9.6 (3.1–22.5)15.8 (7.2–30.0)12.9 (7.9–19.9)9.4 (3.0–21.8)

SAEs of special interest were identified as part of a risk mitigation strategy developed to provide guidance to physicians. Rates of AEs of special interest and common SAEs are shown in Table 3. No cases of opportunistic infection, anaphylaxis, serious hepatic events, or demyelinating events were reported in this study. GI perforations occurred in 3 patients (2 of whom were taking oral steroids); all occurred while the patients were receiving TCZ 4 mg/kg and consisted of 2 large intestine perforations and 1 intestinal abscess. Therefore, the rate of GI perforations per 100 person-years for this study was 0.8 (95% CI 0.2–2.5). One large intestine perforation event resolved without sequelae (the patient had a history of diverticula and did not complete the study treatment), while the other large intestine perforation case resolved with sequelae (the patient completed the study treatment, but subsequently died due to a stroke). The intestinal abscess event resolved with sequelae (the patient had a history of Crohn's disease and did not complete the study treatment).

Table 3. Serious adverse events (SAEs) of special interest and common SAEs*
 TCZ 4/8 mg/kg + DMARDs (n = 364)TCZ 8 mg/kg + DMARDs (n = 381)TCZ 8 mg/kg monotherapy (n = 138)
  • *

    Values are the number (percentage). Common SAEs = >1 patient with the event; TCZ = tocilizumab; DMARDs = disease-modifying antirheumatic drugs (nonbiologic); OI = opportunistic infection.

SAEs of special interest (patients with ≥1 event)   
 Serious infections (including OIs)13 (3.6)15 (3.9)4 (2.9)
 Anaphylaxis000
 Gastrointestinal perforation3 (0.8)00
 Acute myocardial infarction01 (0.3)0
 Stroke1 (0.3)00
 Serious/medically significant hepatic events000
 Spontaneous/serious bleeding1 (0.3)1 (0.3)0
 Demyelination-related events000
 Malignant neoplasms01 (0.3)0
SAEs   
 Serious infection   
  Pneumonia3 (0.8)5 (1.3)1 (0.7)
  Cellulitis3 (0.8)3 (0.8)2 (1.4)
  Osteomyelitis2 (0.5)00
  Sepsis02 (0.5)0
 Cardiovascular/renal/pulmonary   
  Chronic obstructive pulmonary disease1 (0.3)1 (0.3)1 (0.7)
  Cardiac failure, congestive2 (0.5)1 (0.3)0
  Chest pain1 (0.3)01 (0.7)
  Coronary artery disease2 (0.5)00
  Renal failure, acute1 (0.3)1 (0.3)0
 Gastrointestinal   
  Small intestine obstruction1 (0.3)01 (0.7)
  Large intestine perforation2 (0.5)00

A qualitative assessment of SAE risk indicated that current therapy with biologic agents (<2 months prior to enrollment) was not associated with an increased SAE risk compared to previous therapy (≥2 months) or no prior therapy with biologic agents. In patients who never had previous therapy with biologic agents (n = 245), SAEs occurred in 22 patients (9.0%) overall (12 [9.5%] in the TCZ 4/8 mg/kg + DMARDs group, 9 [8.3%] in the TCZ 8 mg/kg + DMARDs group, and 1 [9.1%] in the TCZ 8 mg/kg monotherapy group). In patients who had previously taken ≥1 biologic agents (n = 331), SAEs occurred in 25 patients (7.6%) overall (8 [6.3%], 14 [9.9%], and 3 [4.8%] in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively). In patients currently receiving therapy with biologic agents at study entry (n = 307), SAEs occurred in 22 patients (7.2%) overall (9 [8.1%], 9 [6.9%], and 4 [6.2%] in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively). The rates of SAEs and SIs were also examined in patients who were inadequate responders to DMARDs and biologic agents. The overall rates of SAEs were similar between these 2 groups.

There were 2 deaths reported during the 24-week treatment period, both occurring in the TCZ 4/8 mg/kg + DMARDs arm (both patients received only TCZ 4 mg/kg). The death of a woman age 54 years with preexisting hypertension was caused by cardiac arrest and was considered remotely related to the study medication. The other patient death was a woman age 75 years who had a stroke following a prolonged hospitalization for intestinal perforation (and pelvic abscess) that was considered probably related to study medication.

Safety: laboratory measurements.

The numbers and percentages of patients experiencing laboratory abnormalities of particular interest during the study are shown in Table 4. Of the patients who had an increase in ALT from normal levels at baseline (235 [28.1%] of 836 patients), the majority (193 [82.1%] of 235 patients) were low-grade elevations (≤2 × ULN); 17% (40 of 235 patients) had ALT elevations >2 to 5 × ULN, and 2 patients in the TCZ 8 mg/kg + DMARDs group had ALT levels >5 × ULN. Of the patients with elevated ALT levels, 25.8% discontinued TCZ after the worst occurrence. Grade 3 neutropenia (defined by common toxicity criteria grading as 500 to <1,000/mm3) was reported in 19 patients (2.2%) overall. No patients were reported as having grade 4 neutropenia (<500/mm3), and there was no clear relationship between a low neutrophil count and the occurrence of infections reported as AEs. Grade 3 platelet level reductions (25,000 to <50,000/mm3) were observed in only 2 patients, and no patients were found to have grade 4 platelet reductions (<25,000/mm3).

Table 4. Laboratory values*
 TCZ 4/8 mg/kg + DMARDs (n = 364)TCZ 8 mg/kg + DMARDs (n = 381)TCZ 8 mg/kg monotherapy (n = 138)
  • *

    Values are the number (percentage) unless otherwise indicated. TCZ = tocilizumab; DMARDs = disease-modifying antirheumatic drugs (nonbiologic); ALT = alanine aminotransferase; ULN = upper limit of normal; CTC = common toxicity criteria; ANC = absolute neutrophil count; LLN = lower limit of normal; LDL = low-density lipoprotein.

  • Number of patients with normal value at baseline and at least 1 postbaseline value.

  • ULN defined for ALT as 55 units/liter.

  • §

    Number of patients with at least 1 postbaseline value.

  • Number of patients with baseline value <100 mg/dl and at least 1 postbaseline value.

Change in ALT from normal at baseline to worst value   
 No.340365131
 ≤ULN243 (71.5)250 (68.5)108 (82.4)
 >ULN to 1.5 × ULN63 (18.5)60 (16.4)13 (9.9)
 >1.5 to 2 × ULN20 (5.9)34 (9.3)3 (2.3)
 >2 to 3 × ULN7 (2.1)14 (3.8)5 (3.8)
 >3 to 5 × ULN7 (2.1)5 (1.4)2 (1.5)
 >5 × ULN02 (0.5)0
CTC grade for neutrophil levels, ANC/mm3   
 No.§360378138
 Normal (≥LLN)325 (90.3)282 (74.6)115 (83.3)
 Grade 1 (1,500 to <LLN)17 (4.7)46 (12.2)10 (7.2)
 Grade 2 (1,000 to <1,500)15 (4.2)41 (10.8)6 (4.3)
 Grade 3 (500 to <1,000)3 (0.8)9 (2.4)7 (5.1)
 Grade 4 (<500)000
CTC grade for platelet levels, platelets/mm3   
 No.§360378138
 Normal (≥LLN)314 (87.2)323 (85.4)122 (88.4)
 Grade 1 (75,000 to <LLN)42 (11.7)55 (14.6)15 (10.9)
 Grade 2 (50,000 to <75,000)2 (0.6)01 (0.7)
 Grade 3 (25,000 to <50,000)2 (0.6)00
 Grade 4 (<25,000)000
Shift in LDL cholesterol from baseline <100 mg/dl to last value, mg/dl   
 No.16215062
 <100 (i.e., no change)108 (66.7)94 (62.7)39 (62.9)
 100 to <13041 (25.3)46 (30.7)21 (33.9)
 130 to <16012 (7.4)7 (4.7)2 (3.2)
 160 to <1901 (0.6)3 (2.0)0
 ≥190000

Clinically relevant shifts in low-density lipoprotein (LDL) cholesterol levels from <100 mg/dl at baseline to ≥130 mg/dl at the end of the study occurred in a total of 25 patients (see Table 4 in Supplementary Appendix A for data from all patients, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.21847/abstract). Overall, 182 patients (21%) were receiving treatment with statins at study entry (21% in the TCZ 4/8 mg/kg + DMARDs group, 19% in the TCZ 8 mg/kg + DMARDs group, and 22% in the TCZ 8 mg/kg monotherapy group); 101 patients (11%) initiated statin therapy due to elevation in LDL cholesterol levels during the study (13%, 10%, and 12% of patients in the in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively).

Efficacy outcomes.

Overall, ACR20, ACR50, and ACR70 response rates increased throughout the 24-week treatment period and were similar for the treatment groups (Figure 2A). The mean values for all ACR core parameters were significantly improved (P < 0.0001) from baseline by week 8 and at all subsequent assessments in all treatment groups.

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Figure 2. American College of Rheumatology (ACR) scores over time. A, ACR 20% criteria for improvement (ACR20), ACR 50% criteria for improvement (ACR50), and ACR 70% criteria for improvement (ACR70) response rates over time. B, Percentages of patients originally randomized to the tocilizumab (TCZ) 4 mg/kg + disease-modifying antirheumatic drugs (DMARDs; nonbiologic) group achieving ACR 20 criteria for improvement by dose escalation status. All TCZ doses are in mg/kg.

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Mean DAS28 scores were significantly decreased (P < 0.0001) from baseline at all time points in all treatment groups. At week 24, the mean change in DAS28 score was −1.81 in the TCZ 4/8 mg/kg + DMARDs group, −1.94 in the TCZ 8 mg/kg + DMARDs group, and −2.03 in the TCZ 8 mg/kg monotherapy group. Clinical remission (DAS28 score <2.6) was achieved by week 24 in 59 (20.6%) of 286 patients in the TCZ 4/8 mg/kg + DMARDs group, 76 (25.2%) of 302 patients in the TCZ 8 mg/kg + DMARDs group, and 25 (19.8%) of 126 patients in the TCZ 8 mg/kg monotherapy group. Low disease activity (DAS28 ≤3.2) was achieved by week 24 in 35.3%, 45.7%, and 31.0% of patients in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively.

The TCZ 4/8 mg/kg + DMARDs group included patients who had a TCZ dose increase from 4 mg/kg to 8 mg/kg (+ DMARDs) at or after week 8. The ACR20 response rates increased after week 8 in patients with a dose increase at week 8 (i.e., 1.4%, 28.2%, and 30.3% at weeks 8, 16, and 24, respectively) (Figure 2B). Similar patterns were observed for improvements in the ACR50 and ACR70 response rates following a dose increase at week 8. Among 152 patients who did not increase their TCZ dose, 52.0%, 30.3%, and 12.5% achieved the ACR20, ACR50, and ACR70 criteria, respectively, at week 24.

ACR responses were also similar in patients with an inadequate response to treatment with biologic agents. At week 24, 42.3%, 48.7%, and 46.0% of patients with an inadequate response to biologic agents achieved the ACR20 criteria in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively; 21.4%, 22.8%, and 21.2% achieved the ACR50 criteria in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively; and 6.5%, 8.2%, and 5.8% achieved the ACR70 criteria in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively. Additionally, since an elevated CRP level was not required for study inclusion, joint count responses (at least 20% improvement in both the TJC and SJC) could be examined for patients with a CRP level ≤0.3 mg/dl or >0.3 mg/dl at baseline. In all treatment groups, no association between baseline CRP levels and joint count responses at week 24 was identified.

Mean RAPID-3 scores significantly improved (P < 0.0001) from baseline at all time points for all treatment groups. At week 24, the mean change from baseline in RAPID-3 score was −1.61 for the TCZ 4/8 mg/kg + DMARDs group, −1.46 for the TCZ 8 mg/kg + DMARDs group, and −1.83 for the TCZ 8 mg/kg monotherapy group. Significant improvement (P < 0.0001) in fatigue from baseline was also noted at all time points in all treatment groups. At week 24, the mean change in the patient's global assessment of fatigue was −16.73 for the TCZ 4/8 mg/kg + DMARDs group, −16.07 for the TCZ 8 mg/kg + DMARDs group, and −15.85 for the TCZ 8 mg/kg monotherapy group.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

The safety findings in this clinical trial that was designed to more closely reflect clinical practice were consistent with the previously identified safety profile of TCZ (4–9, 13, 14). Overall, similar rates of SAEs, SIs, and common laboratory abnormalities were observed for patients who received TCZ 8 mg/kg + DMARDs and TCZ 8 mg/kg monotherapy. Additionally, efficacy results across the 3 patient groups were numerically similar.

As observed in the phase III clinical trials, SAEs of special interest were identified, including, for example, GI perforations. Three patients in the TCZ 4/8 mg/kg + DMARDs group developed a GI perforation. To date, a GI perforation rate of 0.20 events per 100 person-years has been observed from a pooled analysis of the 5 randomized phase III trials, a long-term extension of one of these trials, and a drug interaction study. GI perforation events were primarily reported as complications from diverticulitis and occurred mostly in patients taking concomitant nonsteroidal antiinflammatory drugs, corticosteroids, or MTX. Additionally, investigators were provided with recommended dose adjustments of TCZ or concomitant DMARDs in response to changes in liver transaminases, neutrophils, platelets, and cholesterol. In this study, laboratory abnormalities were observed at a rate consistent with other TCZ studies, including elevations of mean total, high-density lipoprotein, and LDL cholesterol levels. Approximately 24% of the patients were taking lipid-lowering agents upon entrance into the study, with statins being most common, and an additional 12% of patients initiated lipid-lowering agents during the study.

Elevations in liver enzymes also occurred at rates consistent with other TCZ studies, and no major hepatic events occurred during the ACT-STAR trial. Of note, ALT elevations were lower in patients receiving TCZ 8 mg/kg monotherapy when compared with patients receiving TCZ 8 mg/kg + DMARDs, which is consistent with results from previous studies (4, 13, 14). Since patients receiving monotherapy experience similar rates of SAEs, SIs, and common laboratory abnormalities, in addition to numerically similar efficacy results, these data continue to support TCZ monotherapy as a potentially valuable treatment option for patients who are unable or unwilling to take DMARDs. Additionally, patients who had an inadequate response to biologic agents, and therefore were potentially treatment refractory, demonstrated numerically similar efficacy results with TCZ 8 mg/kg monotherapy or TCZ 8 mg/kg + DMARDs combination therapy, further supporting the idea that TCZ monotherapy is a viable treatment option.

The ACT-STAR study did not require a washout period for patients who were receiving therapy with biologic agents upon enrollment (with the exception of rituximab). Therefore, the effect of TCZ on the immediate risk of SAEs in patients who were currently receiving biologic agents could be evaluated. The study analyses did not indicate the presence of increased safety risks for patients who entered the study currently receiving a biologic agent compared to patients who previously received biologic agents or never received biologic agents. These results provide evidence that TCZ can be safely initiated following the discontinuation of a biologic agent without a washout period, thereby minimizing the amount of time that a patient would not receive treatment. These results are also consistent with observations from another open-label TCZ trial conducted in a mixed-treatment population outside of the US (15).

In the US, the current prescribing information recommends initiating TCZ at a dose of 4 mg/kg and increasing to 8 mg/kg based on clinical response. Because the safety and efficacy of dose escalation were not studied in the initial phase III clinical trials, they were evaluated here. No apparent higher rates of AEs, SAEs, and SIs were observed post–dose escalation in patients who increased their TCZ dose; however, efficacy outcomes improved in patients who increased their TCZ dose from 4 mg/kg to 8 mg/kg. This improvement was most profound in patients who did not have a 20% improvement in their TJC and SJC at week 8 while receiving TCZ 4 mg/kg + DMARDs. Although the patients who escalated their dose due to joint counts or investigator discretion demonstrated improved efficacy following the dose increase, there were patients who benefited from TCZ 4 mg/kg. Of the patients who were only exposed to TCZ 4 mg/kg, 30% achieved the ACR50 criteria.

There were some limitations to this study. The ACT-STAR study was not designed to demonstrate group differences in efficacy or safety. The 6-month timeframe was potentially not long enough and the sample size was not large enough to detect rare AEs. However, to date, the ACT-STAR study safety data are largely consistent with the phase III randomized trials (including long-term extensions) (4–9). Additionally, patients receiving TCZ 4 mg/kg + DMARDs initially were to have their dose increased to 8 mg/kg at week 8 if they did not achieve a 20% improvement in TJC and SJC. Increasing TCZ at this early time point might have provided results that do not adequately reflect continued improvement in a group of patients who may have required a longer time to respond to the 4 mg/kg dose (16). Finally, this was an open-label study, which may have introduced bias into the results.

In conclusion, in this clinical trial designed to more closely reflect a real-world practice setting, TCZ had an SAE and AE profile consistent with the prior blinded randomized studies and was effective either as monotherapy or in combination with DMARDs for the treatment of RA. TCZ at doses of 4 mg/kg and 8 mg/kg exhibited similar safety signals, including AEs, SAEs, and SIs; however, patients receiving TCZ 8 mg/kg monotherapy had numerically lower rates of ALT elevations. Furthermore, TCZ dose increases from 4 mg/kg to 8 mg/kg were well tolerated by the patients and were frequently accompanied by improvements in efficacy outcomes.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

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. Dr. Weinblatt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Weinblatt, Rigby, Genovese.

Acquisition of data. Kremer, Cush, Rigby, Teng.

Analysis and interpretation of data. Weinblatt, Kremer, Cush, Rigby, Teng, Devenport, Singh, Lepley, Genovese.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

F. Hoffmann-La Roche (Roche) sponsored the study, participated in the design of the study as well as in the collection, analysis, and interpretation of the data. The manuscript was reviewed by Roche, but the decision to submit and publish the manuscript was contingent only upon the approval of the lead author and coauthors, including those employed by Roche. Support for third-party writing assistance for this manuscript, which was provided by Jessica Bessler, PhD, from Health Interactions, was funded by Roche.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

The authors would like to thank Dr. Ray Malamet for his contributions to the study design as well as the data analysis and interpretation.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information
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    Dougados M, Huizinga T, Sheeran T, Tak P, Conaghan P, Navarro-Sarabia F, et al. Tocilizumab (TCZ) plus methotrexate (MTX) does not have superior clinical efficacy to TCZ alone in RA patients with an inadequate response to MTX: 24-week results from the ACT-RAY study [abstract]. Ann Rheum Dis 2011; 70 Suppl 3: 73.
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURES
  10. Acknowledgements
  11. REFERENCES
  12. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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ACR_21847_sm_AppendixA.doc75KSupplementary Appendix A

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