Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Laboratory values from phase III clinical trials of tocilizumab (TCZ) in patients with RA were the basis of the recommendations for monitoring and managing the potential risks associated with laboratory abnormalities. In order to further evaluate and understand the extent and impact of lab abnormalities and their outcomes, additional analyses of the open-label phase IIIB ACT-STAR study, were undertaken.
Methods: ACT-STAR was a prospective, open-label phase IIIB study that evaluated safety, tolerability and efficacy of TCZ monotherapy (Mono) and TCZ + DMARDs in adults with moderate to severe, active RA who were inadequate responders or had safety/tolerability related issues with stable doses of their current DMARDs or biologic based regimens. All patients exposed to TCZ in ACT-STAR were included in this analysis. Scheduled labs were collected and analyzed centrally every 4 weeks during the core study (24 wks + 8wks follow-up) and every 8 wks during the long term extension (eligible patients completing the core study could receive TCZ until ≥3 months after commercial availability). AEs were collected on an ongoing basis. Laboratory abnormalities of interest (LFTs, neutrophils, platelets) were assessed and subsequent AEs, study medication changes and outcomes were evaluated for possible associations.
Results: 883 patients received TCZ treatment in ACT-STAR (TCZ 8 mg/kg Mono, n=138; TCZ 4 mg/kg + DMARD with option to escalate to 8 mg/kg at or after week 8, n=364; TCZ 8 mg/kg + DMARD, n=381). Of the 142 (16.2%) patients with ALT > ULN (55 U/L) or 77 (8.8%) with AST > ULN (40 U/L) for ≥ 2 consecutive scheduled visits, > 50% normalized during the study and most completed the planned treatment and observation period. No cases of drug induced liver injury were reported for either group. Of the 26 (3%) patients with ANC ≤ 1000 cells/mm3 at any point, 81% normalized during study and none experienced serious infections. Similarly, of the 24 (2.7%) patients with platelets ≤ 100,000 cells/mm3 at any point, 75% normalized during study and no serious bleeding events were observed.
Conclusion: Management of patients with RA who receive tocilizumab requires periodic examinations and laboratory monitoring to assess potential risks. In ACT-STAR, no association between lab abnormalities and clinical consequences was observed. Results from this study support the current monitoring guidelines in place in the USPI for TCZ.
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Resolution
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Associations*
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Parameter
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Rate n/N (%)
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Normalized n/N (%)
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Did not normalize n/N (%)
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ALT† Sustained‡ ALT > ULN (55 U/L) |
142/876 (16.2) |
73/142 (51) · 43/73 normalized with medication changes after 2nd consecutive elevation · 30/73 normalized without medication changes after 2nd consecutive elevation |
69/142 (48.6) · 18/69 had no follow-up labs after 2nd consecutive abnormal lab finding (eg., at last visit) · 51/69 had labs after 2nd consecutive elevation [20 had no medication changes; 31 had medication changes]
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No reports of drug-induced liver injury observed at any time point |
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AST† Sustained‡ AST > ULN (40 U/L) |
77/876 (8.8) |
46/77 (60) · 28/46 normalized with medication changes after 2nd consecutive elevation · 18/46 normalized without medication changes after 2nd consecutive elevation |
31/77 (40) · 11/31 had no follow-up labs after 2nd consecutive abnormal lab finding (eg., at last visit) · 20/31 had labs after 2nd consecutive elevation [10 had medication changes; 10 had no medication changes] |
No reports of drug-induced liver injury observed at any time point |
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Neutrophils ANC ≤ 1000 cells/mm3 on at least 1 occasion |
26/876 (3.0) |
21/26 (81) |
5/26 (19) · 5/5 had no follow-up labs after abnormal lab finding (eg., at last visit) |
No serious infections observed at any time point |
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Platelets ≤ 100,000 cells/mm3 on at least 1 occasion Platelets < 50,000-25,000 cells/mm3on at least 1 occasion
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24/876 (2.7) 2/876 (< 1) |
18/24 (75) |
6/24 (25) · 6/6 had no follow-up labs after abnormal lab finding (eg., at last visit) |
No serious bleeding events observed at any time point
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* Associations apply to all patients with the abnormality regardless of normalization status. †LFT parameters were analyzed separately for events or resolution. However, 154 patients had either ALT or AST sustained elevations (12 AST only, 77 ALT only, 65 both). ‡ Sustained is defined as an abnormal value at ≥ 2 consecutive visits. |
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Disclosure:
M. Weinblatt,
Amgen, Abbott, Astra Zeneca, Bristol Myers Squibb, Janssen, UCB, Abbott, Merck, Pfizer and Roche/Genentech,
5;
D. Preston,
Roche/Genetech,
3;
J. Friedman,
Genentech, Inc.,
3;
N. Singh,
Genentech, Inc.,
4;
J. Devenport,
Genentech, Inc.,
3;
J. M. Kremer,
Genentech, Pfizer, Lilly, UCB, Novartis,
2,
Genentech, Pfizer, Lilly, UCB, Novartis,
5.
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