Background
Methods
Study design and population
Study treatment
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SAR200 + 26W taper: Sarilumab 200 mg every 2 weeks (Q2W) subcutaneous (SC) with a 26-week taper of GC.
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SAR150 + 26W taper: Sarilumab 150 mg Q2W SC with a 26-week GC taper.
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PBO + 52W taper: Sarilumab-matching placebo Q2W SC with a 52-week GC taper.
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PBO + 26W taper: Sarilumab-matching placebo Q2W SC with a 26-week GC taper.
Study assessments
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Efficacy: Summary of components of the SR composite measure at week 52 and week 24, total cumulative GC (including prednisone) dose during the treatment period, and time to first GCA flare during the treatment period were measured. In addition, the potential effect of sarilumab on sparing GC toxicity was measured using a glucocorticoid toxicity index (GTI), both as cumulative worsening score (CWS) and aggregate improvement score (AIS) at week 52 and week 24. The composite GTI consists of 9 domains and 31 items that assess the potential side effects of GCs, based on evaluation of body mass index (BMI), glucose tolerance, blood pressure, lipids, bone density, steroid myopathy, skin toxicity, neuropsychiatric toxicity, and infections. The CWS calculates the worsening of GC-associated adverse effects, while the AIS assesses both improvement and worsening [24, 25].
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Safety: Adverse events (AEs), laboratory values, and vital signs were assessed throughout the study.
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Pharmacodynamics (PD): Change from baseline in CRP was measured through week 52, and changes in IL-6 level and soluble IL-6 receptor (sIL-6R) were measured over time from baseline through week 52.
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Pharmacokinetics (PK): Serum functional sarilumab concentrations were determined.
Sample size determination
Changes in conduct of study
Analysis populations
Statistical analyses
Results
Patient disposition
Baseline demographics and disease characteristics
Randomized population (N = 83) | SAR200 + 26W taper (n = 27) | SAR150 + 26W taper (n = 14) | PBO + 52W taper (n = 28) | PBO + 26W taper (n = 14) |
---|---|---|---|---|
Age (years), mean (SD) | 73.4 (8.6) | 67.1 (7.9) | 71.4 (7.7) | 69.5 (5.4) |
Female, n (%) | 23 (85) | 13 (93) | 22 (79) | 9 (64) |
Race, n (%) | ||||
White | 25 (93) | 11 (79) | 23 (82) | 13 (93) |
Black or African American | 0 | 1 (7.1) | 0 | 0 |
Asian | 0 | 0 | 0 | 0 |
Othera | 2 (7) | 2 (14) | 5 (18) | 1 (7) |
BMI (kg/m2) | ||||
N | 27 | 14 | 28 | 13 |
Mean (SD) | 27.2 (5.7) | 27.5 (5.2) | 25.6 (5.0) | 27.8 (4.7)b |
Smoking, n (%) | ||||
Never | 16 (59) | 12 (86) | 20 (71) | 11 (79) |
Current | 2 (7) | 1 (7) | 4 (14) | 2 (14) |
Former | 9 (33) | 1 (7) | 4 (14) | 1 (7) |
GCA, n (%) | ||||
New onset | 14 (52) | 9 (64) | 17 (61) | 8 (57) |
Refractory | 13 (48) | 5 (36) | 11 (39) | 6 (43) |
Disease duration (days)c, median (IQR) | 43.0 (36.0; 273.0) | 39.5 (29.0; 219.0) | 41.0 (28.0; 228.5) | 41.5 (34.0; 343.0) |
Presence of unequivocal GCA cranial symptoms, n (%) | 23 (85) | 10 (71) | 22 (79) | 14 (100) |
Presence of unequivocal PMR symptoms, n (%) | 14 (52) | 11 (79) | 16 (57) | 6 (43) |
GCA diagnosis, n (%) | ||||
N | 26 | 13 | 28 | 14 |
TAB | 8 (31) | 2 (15) | 5 (18) | 8 (57) |
Imaging | 18 (69) | 11 (85) | 23 (82) | 6 (43) |
Imaging methodology, n (%)d | ||||
N | 18 | 11 | 23 | 6 |
CTA | 1 (6) | 0 | 3 (13.0) | 0 |
MRA | 1 (6) | 0 | 1 (4) | 1 (17) |
PET-CT | 3 (17) | 7 (64) | 13 (57) | 4 (67) |
Ultrasound | 13 (72) | 4 (36) | 6 (26) | 1 (17) |
Prednisone dose at baselinee (mg/day), mean (SD) | 34.5 (17.0) | 35.0 (14.7) | 34.6 (12.9) | 30.5 (15.9) |
Randomization strata, n (%) | ||||
< 30 mg/day prednisonee | 12 (44) | 6 (43) | 12 (43) | 6 (43) |
≥ 30 mg/day prednisonee | 15 (56) | 8 (57) | 16 (57) | 8 (57) |
Baseline CRP (mg/L), median (IQR) | 1.6 (0.8; 3.2) | 5.4 (1.1; 11.2) | 2.2 (1.4; 10.6) | 4.0 (2.8; 6.0) |
Baseline ESR (mm/h), median (IQR) | 10.0 (6.0; 28.0) | 19.5 (7.0; 37.0) | 17.0 (10.0; 50.0) | 20.5 (12.0; 22.0) |
Outcome assessments
Primary efficacy endpoint: achievement of sustained remission
n (%) | SAR200 + 26W taper | SAR150 + 26W taper | PBO + 52W taper | PBO + 26W taper |
---|---|---|---|---|
Primary endpoint and sensitivity analyses, n | 13 | 7 | 10 | 6 |
Number of patients achieving SR at week 52 | 6 (46) | 3 (43) | 3 (30) | 0 |
Number of patients achieving SR at week 52 excluding CRP | 6 (46) | 3 (43) | 6 (60) | 1 (17) |
Number of patients achieving SR at week 52 excluding CRP and ESR | 6 (46) | 3 (43) | 6 (60) | 1 (17) |
Additional endpoint and sensitivity analyses, n | 27 | 14 | 28 | 14 |
Number of patients achieving SR at week 24 | 13 (48) | 6 (43) | 11 (39) | 1 (7) |
Number of patients achieving SR at week 24 excluding CRP | 13 (48) | 6 (43) | 16 (57) | 5 (36) |
Number of patients achieving SR at week 24 excluding CRP and ESR | 13 (48) | 6 (43) | 16 (57) | 5 (36) |
Secondary endpoints | ||||
Week 52, n | 13 | 7 | 10 | 6 |
Achievement of disease remission no later than week 12a | 7 (54) | 4 (57) | 7 (70) | 3 (50) |
Absence of disease flare from week 12 through week 52b | 7 (54) | 4 (57) | 7 (70) | 3 (50) |
Sustained reduction of CRP from week 12 through week 52c | 8 (62) | 5 (71) | 6 (60) | 3 (50) |
Successful adherence to the prednisone taper from week 12 through week 52d | 6 (46) | 3 (43) | 6 (60) | 2 (33) |
Week 24, n | 27 | 14 | 28 | 14 |
Achievement of disease remission no later than week 12a | 15 (56) | 9 (64) | 16 (57) | 6 (43) |
Absence of disease flare from week 12 through week 24b | 15 (56) | 10 (71) | 21 (75) | 7 (50) |
Sustained reduction of CRP from week 12 through week 24c | 17 (63) | 11 (79) | 20 (71) | 4 (29) |
Successful adherence to the prednisone taper from week 12 through week 24d | 13 (48) | 7 (50) | 18 (64) | 5 (36) |
Secondary efficacy endpoints
n (%) | SAR200 + 26W taper | SAR150 + 26W taper | PBO + 52W taper | PBO + 26W taper |
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Baseline, n | 27 | 14 | 28 | 14 |
Week 24a | 21 | 14 | 24 | 11 |
Had rescue therapy | 7 (33) | 5 (36) | 5 (21) | 6 (54) |
Due to active GCA | 7 (33) | 5 (36) | 4 (17) | 4 (36) |
Due to elevated ESR attributable to active GCA | 0 | 0 | 1 (4) | 2 (18) |
Week 52a | 12 | 7 | 14 | 7 |
Had rescue therapy | 5 (42) | 4 (57) | 6 (43) | 4 (57) |
Due to active GCA | 5 (42) | 4 (57) | 5 (36) | 2 (29) |
Due to elevated ESR attributable to active GCA | 0 | 0 | 1 (7) | 2 (29) |
Mean (SD) | SAR200 + 26W taper (n = 27) | SAR150 + 26W taper (n = 14) | PBO + 52W taper (n = 28) | PBO + 26W taper (n = 14) |
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Expected cumulative GC dose (mg)a | 1262.6 (512.0) | 1452.0 (464.4) | 2371.6 (785.2) | 1260.4 (487.1) |
Actual cumulative GC dose (mg)b | 1643.1 (967.3) | 2177.1 (1326.7) | 2577.3 (1018.3) | 2270.7 (1418.0) |
Difference between actual and expected cumulative GC dose (mg) | 380.5 (761.7) | 725.1 (1185.4) | 205.7 (742.8) | 1010.2 (1336.8) |
GTI componentsb | SAR200 + 26W taper | SAR150 + 26W taper | PBO + 52W taper | PBO + 26W taper |
---|---|---|---|---|
GTI components at week 52 | ||||
Number at baseline, n | 13 | 7 | 10 | 6 |
Ongoing at week 52, n (%) | 8 (62) | 6 (86) | 9 (90) | 6 (100) |
Missing and imputed, n (%) | 1 (8) | 0 | 3 (30) | 1 (17) |
CWS | ||||
Mean (SD) | 52.8 (39.0) | 77.2 (41.7) | 73.0 (50.3) | 84.7 (33.4) |
Min; max | 10; 150 | 20; 127 | 0; 145 | 51; 141 |
AIS | ||||
Mean (SD) | -0.5 (51.5) | 23.7 (31.9) | -19.5 (65.0) | 31.2 (54.7) |
Min; max | -142; 40 | -11; 69 | -157; 49 | -54; 90 |
GTI components at week 24 | ||||
Number at baseline, n | 27 | 14 | 28 | 14 |
Ongoing at week 24, n (%) | 18 (67) | 13 (93) | 24 (86) | 9 (64) |
Missing and imputed, n (%) | 1 (4) | 2 (14) | 3 (11) | 2 (14) |
CWS | ||||
Mean (SD) | 31.0 (42.9) | 55.1 (43.1) | 29.2 (30.8) | 30.7 (33.2) |
Min; max | 0; 196 | 10; 166 | 0; 115 | 0; 103 |
AIS | ||||
Mean (SD) | -3.3 (43.4) | 14.2 (55.0) | -21.6 (54.8) | -13.4 (44.3) |
Min; max | -109; 112 | -43; 166 | -156; 74 | -115; 65 |
Safety
PT, n (%)a | SAR200 + 26W taper (n = 27) | SAR150 + 26W taper (n = 14) | PBO + 52W taper (n = 28) | PBO + 26W taper (n = 14) |
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Treatment-emergent SAE | 7 (26) | 2 (14) | 2 (7) | 3 (21) |
COVID-19 | 1 (4) | 0 | 0 | 0 |
Cellulitis | 1 (4) | 0 | 0 | 0 |
Urosepsis | 1 (4) | 0 | 0 | 0 |
Lower respiratory tract infection | 0 | 0 | 1 (4) | 0 |
Pyelonephritis | 0 | 0 | 0 | 1 (7) |
Septic shock | 0 | 0 | 0 | 1 (7) |
Neutropenia | 2 (7) | 0 | 0 | 0 |
Cerebral amyloid angiopathy | 1 (4) | 0 | 0 | 0 |
Blindness unilateral | 0 | 1 (7) | 0 | 0 |
Retinal artery occlusion | 0 | 1 (7) | 0 | 0 |
Aortic dissection | 1 (4) | 0 | 0 | 0 |
Deep vein thrombosis | 0 | 0 | 1 (4) | 0 |
Peripheral vascular disorder | 0 | 0 | 0 | 1 (7) |
Acute respiratory failure | 0 | 0 | 0 | 1 (7) |
Colitis ulcerative | 0 | 0 | 1 (4) | 0 |
Hiatus hernia | 0 | 1 (7) | 0 | 0 |
Femur fracture | 1 (4) | 0 | 0 | 0 |
TEAE leading to permanent treatment discontinuation | 7 (26) | 1 (7) | 2 (7) | 1 (7) |
COVID-19 | 1 (4) | 0 | 0 | 0 |
Cellulitis | 1 (4) | 0 | 0 | 0 |
Ovarian adenoma | 0 | 1 (7) | 0 | 0 |
Neutropenia | 2 (7) | 0 | 0 | 0 |
Thyroid cyst | 0 | 0 | 1 (4) | 0 |
Cerebral amyloid angiopathy | 1 (4) | 0 | 0 | 0 |
Headache | 1 (4) | 0 | 0 | 0 |
Atrial fibrillation | 1 (4) | 0 | 0 | 0 |
Acute respiratory failure | 0 | 0 | 0 | 1 (7) |
Gastrointestinal disorder | 1 (4) | 0 | 0 | 0 |
Colitis ulcerative | 0 | 0 | 1 (4) | 0 |
Alanine aminotransferase increased | 1 (4) | 0 | 0 | 0 |
AESI | 6 (22) | 1 (7) | 2 (7) | 1 (7) |
Herpes ophthalmic | 1 (4) | 0 | 0 | 0 |
Herpes zosterb | 0 | 1 (7) | 1 (4) | 0 |
Cellulitis | 1 (4) | 0 | 0 | 0 |
COVID-19 | 1 (4) | 0 | 0 | 0 |
Cellulitis | 1 (4) | 0 | 0 | 0 |
Herpes zosterc | 0 | 0 | 1 (4) | 0 |
Lower respiratory tract infection | 0 | 0 | 1 (4) | 0 |
Pyelonephritis | 0 | 0 | 0 | 1 (7) |
Septic shock | 0 | 0 | 0 | 1 (7) |
ALT increasedd | 1 (4) | 0 | 0 | 0 |
Neutropenia | 2 (7) | 0 | 0 | 0 |
ALT increasede | 1 (4) | 0 | 0 | 0 |