TY - JOUR
T1 - Concordance and discordance in SLE clinical trial outcome measures
T2 - Analysis of three anifrolumab phase 2/3 trials
AU - Bruce, Ian N.
AU - Furie, Richard A.
AU - Morand, Eric F.
AU - Manzi, Susan
AU - Tanaka, Yoshiya
AU - Kalunian, Kenneth C.
AU - Merrill, Joan T.
AU - Puzio, Patricia
AU - Maho, Emmanuelle
AU - Kleoudis, Christi
AU - Albulescu, Marius
AU - Hultquist, Micki
AU - Tummala, Raj
N1 - Funding Information:
Acknowledgements The authors would like to thank the investigators, research staff, healthcare providers, patients and caregivers who contributed to this study. The authors would like to thank Emma Witch of Audubon and Konstantina Psachoulia of AstraZeneca for their support and diligence for interpretation of patient-level analyses. Medical writing and editing assistance were provided by Rosie Butler, PhD, of JK Associates Inc., part of Fishawack Health. This support was funded by AstraZeneca. INB is a National Institute for Health Research (NIHR) Senior Investigator Emeritus and is funded by the NIHR Manchester Biomedical Research Centre. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
Funding Information:
The study was sponsored by AstraZeneca.
Funding Information:
Competing interests INB has received grant/research support from Genzyme/ Sanofi, GSK, Roche and UCB; received consulting fees from AstraZeneca, Eli Lilly, GSK, ILTOO, Merck Serono and UCB; and speaker/honoraria from AstraZeneca, GSK and UCB. INB is a National Institute for Health Research (NIHR) Senior Investigator Emeritus and is funded by the NIHR Manchester Biomedical Research Centre. RAF has received grant/research support and consulting fees from AstraZeneca. EFM received grant support from AstraZeneca, Bristol Myers Squibb, Janssen, Merck Serono and UCB; was a consultant for AstraZeneca, Eli Lilly, Janssen and Merck Serono; and was a speaker at a speaker bureau for AstraZeneca. SM has received grants and other support and has been a member of an advisory board for AstraZeneca. YT has received speaking fees and/or honoraria from AbbVie, Asahi Kasei, Astellas, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi and YL Biologics, and has received research grants from AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Takeda and UCB. KCK has received consulting fees from AbbVie, Amgen, AstraZeneca, Biogen, Chemocentryx, Eli Lilly, Equillium, Genentech/Roche, GSK, Janssen and Nektar; and has received grant/research support from BMS, Irdosia, Kirin, Pfizer, Resolve, Takeda and UCB. JTM has received grant/research support from BMS and GSK and has received consulting fees from AstraZeneca, AbbVie, Amgen, Aurinia, BMS, EMD Serono, GSK, Remegen, Janssen, Provention and UCB. PP, EM, CK, MA, MH and RT are employees of AstraZeneca.
Publisher Copyright:
© Author(s) (or their employer(s)) 2022.
PY - 2022/7
Y1 - 2022/7
N2 - Objectives In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results. Methods TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient. Results Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients. Conclusions Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials. Trial registration numbers NCT02446912 and NCT02446899.
AB - Objectives In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results. Methods TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient. Results Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients. Conclusions Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials. Trial registration numbers NCT02446912 and NCT02446899.
KW - Autoimmune Diseases
KW - Biological Therapy
KW - Lupus Erythematosus, Systemic
UR - https://www.scopus.com/pages/publications/85132311657
U2 - 10.1136/annrheumdis-2021-221847
DO - 10.1136/annrheumdis-2021-221847
M3 - Article
C2 - 35580976
AN - SCOPUS:85132311657
SN - 0003-4967
VL - 81
SP - 962
EP - 969
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 7
ER -