When data from 12 registrational trials conducted in patients with psoriasis, psoriatic arthritis (PsA), and Crohn’s disease (CD) were combined, discontinuations due to adverse events (AEs) and incidences of AEs, serious AEs, and infections were consistent between ustekinumab- and placebo-treated patients through up to 1 year of follow-up. |
Among ustekinumab-treated patients, incidences of major adverse cardiovascular events, malignancies, and deaths through 1 year were low (≤ 0.5/100 patient-years); the occurrence of infections through 1 year did not appear to be affected by baseline methotrexate or corticosteroid use. |
In this integrated cohort of 5884 ustekinumab-treated patients, ustekinumab demonstrated a favorable integrated safety profile, consistent with previous safety observations from trials within each indication. |
1 Introduction
Study phase/identifier (dates) | Treatment groups/numbers of patients |
---|---|
Moderate-to-severe plaque psoriasis (no concomitant CSs/IMMs)
| |
Phase II/ NCT00320216 (11/2003–3/2005) [23] | Placebo weekly × 4 SC doses (n = 64)a |
Ustekinumab 45 mg single SC dose—week 0 (n = 64) | |
Ustekinumab 90 mg single SC dose—week 0 (n = 64) | |
Ustekinumab 45 mg weekly × 4 SC doses (n = 64) | |
Ustekinumab 90 mg weekly × 4 SC doses (n = 64) | |
Phase III/PHOENIX-1 NCT00267969 (12/2005–5/2011) [5] | Placebo SC (weeks 0 and 4) → ustekinumab 45 mg SC—weeks 12 and 16 then q12w (n = 123) |
Placebo SC (weeks 0 and 4) → ustekinumab 90 mg SC—weeks 12 and 16 then q12w (n = 120) | |
Ustekinumab 45 mg SC—weeks 0 and 4 then q12w (n = 255) | |
Ustekinumab 90 mg SC—weeks 0 and 4 then q12w (n = 256) | |
At week 28, PASI75 responders continued 45 or 90 mg, q12w; PASI50–75 partial responders switched to 45 or 90 mg q8w | |
At week 40, PASI75 responders initially randomized to ustekinumab were re-randomized to placebo or 45/90 mg q12w; PASI75 responders initially randomized to placebo withdrew from treatment; PASI75 partial responders initially randomized to placebo switched from q12w → q8w dosing | |
Phase III/PHOENIX-2 NCT00307437 (5/2005–10/2011) [6] | Placebo SC (weeks 0 and 4) → ustekinumab 45 mg SC—weeks 12 and 16 then q12w (n = 197) |
Placebo SC (weeks 0 and 4) → ustekinumab 90 mg SC—weeks 12 and 16 then q12w (n = 195) | |
Ustekinumab 45 mg SC—weeks 0 and 4 then q12w (n = 409) | |
Ustekinumab 90 mg SC—weeks 0 and 4 then q12w (n = 411) | |
At week 28, PASI50–75 partial responders were randomized to maintain their originally assigned dose (45 or 90 mg) at q12w intervals or dose-adjusted to q8w | |
Phase III/ACCEPT NCT00454584 (3/2007–1/2009) [7] | Etanercept 50 mg SC twice weekly for 12 weeks (n = 347)b |
Ustekinumab 45 mg SC—weeks 0 and 4 (n = 209)b | |
Ustekinumab 90 mg SC—weeks 0 and 4 (n = 347)b | |
Active psoriatic arthritis (with or without CSs/MTX)
| |
Phase II/ NCT00267956 (12/2005–9/2007) [24] | Placebo SC—weeks 0, 1, 2, and 3 → ustekinumab 90 mg SC—weeks 12 and 16 (n = 70) |
Ustekinumab 90 mg SC—weeks 0, 1, 2, and 3 → placebo SC—weeks 12 and 16 (n = 76) | |
Inclusion of up to 25% of patients previously treated with anti-TNF agents allowed | |
Phase III/PSUMMIT-1 NCT01009086 (12/2009–5/2013) [8] | Placebo SC—weeks 0, 4, 16, and 20) → ustekinumab 45 mg SC—weeks 24 and 28 then q12w (n = 206) |
Ustekinumab 45 mg SC—weeks 0 and 4 then q12w (n = 205) | |
Ustekinumab 90 mg SC—weeks 0 and 4 then q12w (n = 204) | |
Naïve to anti-TNF agents | |
Phase III/PSUMMIT-2 NCT01077362 (3/2010–11/2012) [9] | Placebo SC—weeks 0, 4, 16, and 20 → ustekinumab 45 mg SC—weeks 24 and 28 then q12w (n = 104) |
Ustekinumab 45 mg SC—weeks 0 and 4 then q12w (n = 103) | |
Ustekinumab 90 mg SC—weeks 0 and 4 then q12w (n = 105) | |
Inclusion of 50–60% of patients previously treated with anti-TNF agents allowed | |
Moderately-to-severely active Crohn’s Disease (with or without concomitant CSs/IMMs)
| |
Phase IIa NCT00265122 (4/2004–10/2006) [21] | Population 1—active disease despite treatment with conventional therapy (n = 104): |
Ustekinumab 90 mg SC—weeks 0, 1, 2 and 3; placebo SC—weeks 8, 9, 10, and 11 (n = 25) | |
Placebo SC—weeks 0, 1, 2, and 3; ustekinumab 90 mg SC—weeks 8, 9, 10, and 11 (n = 26) | |
Ustekinumab 4.5 mg/kg IV—week 0; placebo IV—week 8 (n = 26) | |
Placebo IV—week 0; ustekinumab 4.5 mg/kg IV—week 8 (n = 27) | |
Population 2—failure to respond to, or loss of response to, infliximab at the maximum approved dose and treatment regimen for CD (n = 27): | |
Ustekinumab 90 mg SC—weeks 0, 1, 2, and 3 (n = 14) | |
Ustekinumab 4.5 mg/kg IV—week 0 (n = 13) | |
Phase IIb/CERTIFI NCT00771667 (12/2008–12/2010) [22] | Randomized IV induction phase: |
Placebo (n = 132); ustekinumab 1 mg/kg (n = 131); ustekinumab 3 mg/kg (n = 132); ustekinumab 6 mg/kg (n = 131) | |
SC maintenance phase (based on clinical response to IV induction at week 6): | |
Responders—randomized to: placebo—weeks 8 and 16 (n = 73); ustekinumab 90 mg SC—weeks 8 and 16 (n = 72) | |
Non-responders—randomized to: ustekinumab 90 mg SC (n = 109); placebo (n = 110) | |
Non-randomized patients (n = 113): placebo—weeks 8 and 16 (responders to placebo IV induction, n = 28); Ustekinumab 270 mg SC—week 8, and 90 mg SC—week 16 (non-responders to placebo IV induction, n = 85) | |
Patients who did not respond initially, responded initially but then lost response, or were intolerant of prior infliximab, adalimumab, or certolizumab pegol | |
Phase III/UNITI-1 NCT01369329 (7/2011–7/2013) [11] | Single IV induction dose at week 0 (n = 741; 769 totalc): placebo (n = 247); ustekinumab 130 mg (n = 245); tiered (weight-based) ustekinumab doses approximately 6 mg/kg (n = 249) |
Patients who did not respond initially, responded initially but then lost response, or were intolerant of prior infliximab, adalimumab, or certolizumab pegol | |
Phase III/UNITI-2 NCT01369342 (7/2011–10/2014) [11] | Single IV induction dose at week 0 (n = 628; 640 totald): |
Placebo (n = 210); ustekinumab 130 mg (n = 209); tiered ustekinumab doses approximately 6 mg/kg (n = 209) | |
Patients had active inflammation and demonstration of inadequate response to, or failure to tolerate, CSs/IMMs; patients with CS dependence and who received but did not fail a TNF antagonist were allowed | |
Phase III/IM-UNITI NCT01369355 (9/2011–10/2019) [11] | Randomized (responders to ustekinumab IV induction, n = 397): |
Placebo SC (n = 133);e ustekinumab 90 mg SC q12w (n = 132); ustekinumab 90 mg SC q8w (n = 132) | |
Non-randomized (n = 884): | |
Placebo SC (responders to placebo IV induction, n = 123) | |
Non-responders to ustekinumab IV induction (n = 476): ustekinumab 90 mg SC week 0 → discontinued at week 8 (n = 221); ustekinumab 90 mg SC week 0 → 90 mg SC q8w (n = 255) | |
Non-responders to placebo IV induction (n = 285): ustekinumab 130 mg IV—week 0 → discontinued at week 8 (n = 121); ustekinumab 130 mg IV—week 0 → 90 mg SC q12w (n = 164) | |
Patients from both phase III induction studies could continue into this maintenance study, with the primary population comprising responders to IV ustekinumab induction therapy |
2 Patients and Methods
2.1 Trial Designs
Psoriasis | PsA | CD | All patients | |
---|---|---|---|---|
Number of randomized patients, Na | 3219 | 1073 | 1988 | 6280 |
Baseline demographics
| ||||
Age, years [mean (SD)] | 45.6 (12.37) | 47.6 (11.87) | 38.6 (12.73) | 43.7 (12.90) |
Male [n (%)] | 2207 (68.6) | 560 (52.2) | 871 (43.8) | 3638 (57.9) |
White [n (%)] | 2960 (92.0) | 1038 (96.8) | 1729 (87.0) | 5727 (91.2) |
Weight, kg [mean (SD)] | 91.8 (22.15) | 89.4 (21.07) | 72.2 (19.64) | 85.2 (22.99) |
BMI, kg/m2 [mean (SD)] | 30.9 (6.99) | 31.0 (7.13) | 25.0 (6.22) | 29.0 (7.32) |
Medical history and current diagnoses,
b
[% (n/N)]
| ||||
Congestive heart failurec [% (n/N)] | 0.2 (5/2899) | 1.1 (12/1073) | 0.4 (7/1935) | 0.4 (24/5907) |
Peripheral vascular diseasec [% (n/N)] | 1.2 (35/2899) | 3.4 (36/1073) | 1.5 (29/1935) | 1.7 (100/5907) |
Transient ischemic attackc [% (n/N)] | 0.8 (24/2899) | 1.0 (11/1073) | 0.8 (15/1935) | 0.8 (50/5907) |
Strokec [% (n/N)] | 0.6 (17/2899) | 1.4 (15/1073) | 0.7 (14/1935) | 0.8 (46/5907) |
Ischemic heart/coronary artery disease [% (n/N)] | 3.9 (125/3219) | 5.7 (61/1073) | 2.3 (44/1935) | 3.7 (230/6227) |
Hyperlipidemia [% (n/N)] | 20.2 (649/3219) | 17.6 (189/1073) | 5.8 (113/1935) | 15.3 (951/6227) |
Hypertension [% (n/N)] | 27.5 (886/3219) | 38.1 (409/1073) | 13.6 (264/1935) | 25.0 (1559/6227) |
Diabetes mellitus [% (n/N)] | 10.6 (342/3219) | 12.0 (129/1073) | 3.2 (61/1935) | 8.5 (532/6227) |
Family history of early coronary artery diseasec [% (n/N)] | 11.7 (340/2899) | 8.7 (93/1073) | 7.3 (142/1935) | 9.7 (575/5907) |
Current smokingc [% (n/N)] | 33.2 (963/2899) | 21.4 (230/1073) | 24.7 (491/1988) | 28.3 (1684/5960) |
Prior biologic treatmentc [% (n/N)] | 33.1 (961/2899) | 20.5 (220/1073) | 77.5 (1499/1935) | 45.4 (2680/5907) |
Baseline concomitant therapies [n (%)]d | ||||
Corticosteroids | – | 146 (13.6) | 728 (36.6) | 874 (13.9) |
Immunomodulators | – | 482 (44.9) | 605 (30.4) | 1087 (17.3) |
6-MP/AZAe | – | – | 456 (22.9) | 456 (7.3) |
Methotrexate | – | 482 (44.9) | 155 (7.8) | 637 (10.1) |
Corticosteroids + immunomodulators [n (%)] | – | 100 (9.3) | 201 (10.1) | 301 (4.8) |
Extent of ustekinumab exposure
f
| ||||
Ustekinumab-treated patients (N)g | 3117 | 1018 | 1749 | 5884 |
Ustekinumab exposure [n (%)] | ||||
Single IVh | 0 | 0 | 1664 (95.1) | – |
At least 6 monthsi | 2413 (77.4) | 842 (82.7) | 849 (48.5) | – |
At least 1 yearj | 1142 (36.6) | 527 (51.8) | 464 (26.5) | – |
Mean weeks of treatment | 26.5 | 27.7 | 19.5k | 24.6 |
Total dose, mg [mean (SD)] | 270.4 (122.38) | 264.5 (126.34) | 432.1 (243.86) | 317.4 (184.2) |
2.2 Safety Outcomes
2.3 Data Analysis
3 Results
3.1 Baseline Patient Demographics, Medical History, Concomitant Medications
Placebo-controlled periods | ||||||||
---|---|---|---|---|---|---|---|---|
Psoriasis (0–12 weeks)a | PsA (0–16 weeks)a | CD (0–8 weeks)a | All patients | |||||
Placebo | Ustekinumab | Placebo | Ustekinumab | Placebo | Ustekinumab | Placebo | Ustekinumab | |
Number of patients treated | 732 | 1582 | 379 | 692 | 624 | 1362 | 1735 | 3636 |
Mean weeks of follow-up | 12.57 | 13.37 | 15.14 | 15.70 | 8.15 | 8.16 | 11.54 | 11.86 |
Mean number of administrationsb | 2.21 | 2.12 | 2.29 | 2.20 | 1.00 | 1.00 | 1.79 | 1.72 |
D/C study drug due to AEs [n (%)] | 17 (2.3) | 24 (1.5) | 15 (4.0) | 8 (1.2) | 27 (4.3) | 26 (1.9) | 59 (3.4) | 58 (1.6) |
PYs of follow-up | 177 | 407 | 110 | 209 | 98 | 214 | 385 | 829 |
Event rate/100 PYs | ||||||||
AEs | 415.5 | 511.3 | 352.4 | 382.4 | 1040.4 | 959.4 | 556.1 | 594.3 |
95% CIc | 386.0–446.7 | 489.5–533.7 | 318.3–389.3 | 356.4–409.9 | 977.5–1106.4 | 918.3–1001.9 | 532.8–580.1 | 577.9–611.2 |
SAEs | 6.8 | 7.9 | 12.7 | 6.2 | 50.1 | 42.6 | 19.5 | 16.4 |
95% CIc | 3.5–11.9 | 5.4–11.1 | 6.9–21.3 | 3.3–10.6 | 37.1–66.3 | 34.3–52.3 | 15.3–24.4 | 13.8–19.4 |
Infectionsd | 122.1 | 141.4 | 112.3 | 100.5 | 187.2 | 168.4 | 135.8 | 138.1 |
95% CIc | 106.4–139.5 | 130.1–153.5 | 93.4–134.0 | 87.4–115.1 | 161.1–216.4 | 151.5–186.7 | 124.4–148.0 | 130.2–146.3 |
Serious infectionsd | 1.6 | 1.2 | 0.9 | 0.0 | 7.2 | 10.3 | 2.9 | 3.3 |
95% CIc | 0.4–5.0 | 0.4–2.9 | 0.0–5.1 | 0.0–1.4 | 2.9–14.8 | 6.5–15.6 | 1.4–5.1 | 2.2–4.7 |
Adjudicated serious MACE | 0.0 | 1.2 | 0.9 | 0.0 | 0.0 | 0.0 | 0.3 | 0.6 |
95% CIc | 0.0–1.7 | 0.4–2.9 | 0.0–5.1 | 0.0–1.4 | 0.0–3.1 | 0.0–1.4 | 0.0–1.5 | 0.2–1.4 |
Deaths | 0.0 | 0.3 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.1 |
95% CIc | 0.0–1.7 | 0.0–1.4 | 0.0–2.7 | 0.0–1.4 | 0.0–3.1 | 0.0–1.4 | 0.0–0.8 | 0.0–0.7 |
Malignancies (excluding NMSC) | 0.6 | 0.3 | 0.0 | 0.0 | 0.0 | 0.0 | 0.3 | 0.1 |
95% CIc | 0.0–3.2 | 0.0–1.4 | 0.0–2.7 | 0.0–1.4 | 0.0–3.1 | 0.0–1.4 | 0.0–1.5 | 0.0–0.7 |
Through approximately year 1e | ||||||||
---|---|---|---|---|---|---|---|---|
Psoriasis | PsA | CD | All patients | |||||
Placebof | Ustekinumabg | Placeboh | Ustekinumabi | Placeboj | Ustekinumabk | Placebo | Ustekinumab | |
Number of patients treated | 733 | 3117 | 379 | 1018 | 943 | 1749 | 2055 | 5884 |
Mean weeks of follow-up | 12.93 | 42.80 | 19.90 | 43.40 | 19.12 | 32.89 | 17.05 | 39.96 |
Mean weeks of treatment | 4.90 | 26.49 | 11.96 | 27.66 | 9.87 | 18.80 l | 8.41 | 24.41 |
D/C study drug due AEs [n (%)] | 17 (2.3) | 86 (2.8) | 22 (5.8) | 31 (3.0) | (4.8) | 108 (6.2) | 84 (4.1) | 225 (3.8) |
PYs of follow-up | 182 | 2,566 | 145 | 850 | 347 | 1,106 | 674 | 4,521 |
Event rate/100 PYs | ||||||||
AEs | 414.8 | 390.6 | 343.4 | 254.2 | 712.2 | 641.6 | 552.4 | 426.4 |
95% CIc | 385.8–445.5 | 383.0–398.3 | 313.9–374.9 | 243.6–265.2 | 684.3–740.8 | 626.8–656.7 | 534.8–570.4 | 420.4–432.5 |
SAEs | 8.8 | 8.8 | 13.8 | 9.3 | 43.8 | 35.4 | 27.9 | 15.4 |
95% CIc | 5.0–14.3 | 7.7–10.0 | 8.4–21.3 | 7.4–11.6 | 37.2–51.4 | 31.9–39.0 | 24.1–32.2 | 14.3–16.6 |
Infectionsd | 120.7 | 137.4 | 102.8 | 78.0 | 145.1 | 134.0 | 129.4 | 125.4 |
95% CIc | 105.3–137.8 | 132.9–142.0 | 86.9–120.6 | 72.2–84.2 | 132.7–158.3 | 127.3–141.0 | 120.9–138.3 | 122.2–128.7 |
Serious infectionsd | 1.6 | 1.4 | 0.7 | 0.9 | 6.9 | 6.4 | 4.2 | 2.5 |
95% CIc | 0.3–4.8 | 1.0–1.9 | 0.0–3.8 | 0.4–1.9 | 4.4–10.3 | 5.0–8.1 | 2.8–6.0 | 2.1–3.1 |
Adjudicated serious MACE | 0.6 | 0.6 | 0.7 | 0.7 | 0.0 | 0.1 | 0.3 | 0.5 |
95% CIc | 0.0–3.1 | 0.3–0.9 | 0.0–3.8 | 0.3–1.5 | 0.0–0.9 | 0.0–0.5 | 0.0–1.1 | 0.3–0.7 |
Deaths | 0.0 | 0.2 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.1 |
95% CIc | 0.0–1.6 | 0.1–0.5 | 0.0–2.1 | 0.0–0.4 | 0.0–0.9 | 0.0–0.3 | 0.0–0.4 | 0.0–0.3 |
Malignancies (excluding NMSC) | 0.6 | 0.4 | 0.0 | 0.1 | 0.0 | 0.4 | 0.2 | 0.4 |
95% CIc | 0.0–3.1 | 0.2–0.8 | 0.0–2.1 | 0.0–0.7 | 0.0–0.9 | 0.1–0.9 | 0.0–0.8 | 0.2–0.6 |
3.2 Adverse Events (AEs)/Serious AEs, Including Infections, and AEs Leading to Study Drug Discontinuation
3.2.1 Initial Controlled Period
3.2.2 Year 1 Analyses
Through week 8 of UNITI-1 and UNITI-2 | Through week 44 or time of dose adjustment in IM-UNITI | |||||||
---|---|---|---|---|---|---|---|---|
Ustekinumab | Ustekinumabb | |||||||
Placebo | 130 mg IV | 6 mg/kg IV | Combined | Placebo SCa,b | 90 mg SC q12w | 90 mg SC q8w | Combined | |
Number of patients randomized and treated | 466 | 471 | 470 | 941 | 133 | 132 | 131 | 263 |
Mean weeks of follow-up | 8.18 | 8.22 | 8.16 | 8.19 | 32.0 | 36.6 | 35.2 | 35.9 |
Number (%) of patients with: | ||||||||
AEs | 282 (60.5) | 275 (58.4) | 284 (60.4) | 559 (59.4) | 111 (83.5) | 106 (80.3) | 107 (81.7) | 213 (81.0) |
SAEs | 28 (6.0) | 23 (4.9) | 25 (5.3) | 48 (5.1) | 20 (15.0) | 16 (12.1) | 13 (9.9) | 29 (11.0) |
Infectionsc | 108 (23.2) | 92 (19.5) | 111 (23.6) | 203 (21.6) | 66 (49.6) | 61 (46.2) | 63 (48.1) | 124 (47.1) |
Serious infectionsc | 6 (1.3) | 7 (1.5) | 8 (1.7) | 15 (1.6) | 3 (2.3) | 7 (5.3) | 3 (2.3) | 10 (3.8) |
D/C study drug due to AEs | 19 (4.1) | 8 (1.7) | 8 (1.7) | 16 (1.7) | 8 (6.0) | 10 (7.6) | 4 (3.1) | 14 (5.3) |
3.2.3 Baseline Medications
PsA | CD | PsA and CD combined | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Placeboa | Ustekinumabb | Placeboc | Ustekinumabd | Placebo | Ustekinumab | |||||||
+MTX | −MTX | +MTX | −MTX | +MTX | −MTX | +MTX | −MTX | +MTX | −MTX | +MTX | −MTX | |
Number of patients treated | 160 | 219 | 465 | 553 | 76 | 867 | 139 | 1610 | 236 | 1086 | 604 | 2163 |
Mean weeks of follow-up | 20.78 | 19.25 | 44.28 | 42.65 | 17.16 | 19.29 | 33.36 | 32.84 | 19.62 | 19.28 | 41.77 | 35.35 |
Mean weeks of treatment | 13.93 | 10.51 | 29.32 | 26.25 | 7.23 | 10.08 | 19.67 | 18.72 | 12.02 | 10.18 | 27.10 | 20.65 |
D/C study drug due to AEs [n (%)] | 8 (5.0) | 14 (6.4) | 16 (3.4) | 15 (2.7) | 3 (3.9) | 42 (4.8) | 9 (6.5) | 99 (6.1) | 11 (4.7) | 56 (5.2) | 25 (4.1) | 114 (5.3) |
PYs of follow-up | 64 | 81 | 396 | 454 | 25 | 322 | 89 | 1017 | 89 | 403 | 485 | 1470 |
Event rate/100 PYS | ||||||||||||
AEs | 381.5 | 313.3 | 255.6 | 253.1 | 849.5 | 701.5 | 647.0 | 641.2 | 513.3 | 632.3 | 327.5 | 521.5 |
95% CIe | 335.2–432.5 | 276.0–354.3 | 240.1–271.8 | 238.7–268.2 | 739.2–971.5 | 672.8–731.0 | 595.2–702.0 | 625.7–656.9 | 467.3–562.6 | 599.2–648.2 | 311.6–344.0 | 509.9–533.3 |
SAEs | 20.3 | 8.6 | 6.8 | 11.5 | 79.8 | 41.0 | 40.4 | 34.9 | 37.1 | 34.5 | 13.0 | 27.7 |
95% CIe | 10.8–34.8 | 3.5–17.8 | 4.5–9.9 | 8.6–15.0 | 48.7–123.2 | 34.3–48.7 | 28.3–55.9 | 31.4–38.7 | 25.5–52.1 | 29.0–40.8 | 10.0–16.6 | 25.1–30.5 |
Infectionsf | 104.8 | 101.2 | 82.3 | 74.3 | 139.6 | 145.5 | 137.9 | 133.6 | 114.6 | 136.6 | 92.5 | 115.3 |
95% CIe | 81.2–133.1 | 80.5–125.6 | 73.6–91.8 | 66.6–82.7 | 97.2–194.1 | 132.6–159.3 | 114.6–164.6 | 126.6–140.9 | 93.4–139.1 | 125.4–148.5 | 84.2–101.5 | 109.9–121.0 |
Serious infectionsf | 1.6 | 0.0 | 0.0 | 1.8 | 16.0 | 6.2 | 13.5 | 5.8 | 5.6 | 5.0 | 2.5 | 4.6 |
95% CIh | 0.0–8.7 | 0.0–3.7 | 0.0–0.8 | 0.8–3.5.5 | 4.4–40.9 | 3.8–9.6 | 7.0–23.5 | 4.4–7.5 | 1.8–13.1 | 3.0–7.7 | 1.3–4.3 | 3.5–5.8 |
Adjudicated serious MACE | 0.0 | 1.2 | 0.3 | 1.1 | 0.0 | 0.0 | 0.0 | 0.1 | 0.0 | 0.3 | 0.2 | 0.4 |
95% CIe | 0.0–4.7 | 0.0–6.9 | 0.0–1.4 | 0.4–2.6 | 0.0–12.0 | 0.0–0.9 | 0.0–3.4 | 0.0–0.6 | 0.0–3.4 | 0.0–1.4 | 0.0–1.2 | 0.2–0.9 |
Deaths | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
95% CIe | 0.0–4.7 | 0.0–3.7 | 0.0–0.8 | 0.0–0.7 | 0.0–12.0 | 0.0–0.9 | 0.0–3.4 | 0.0–0.3 | 0.0–3.4 | 0.0–0.7 | 0.0–0.6 | 0.0–0.2 |
Malignancies (excluding NMSC) | 0.0 | 0.0 | 0.0 | 0.2 | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 0.3 |
95% CIe | 0.0–4.7 | 0.0–3.7 | 0.0–0.8 | 0.0–1.2 | 0.0–12.0 | 0.0–0.9 | 0.0–3.4 | 0.1–1.0 | 0.0–3.4 | 0.0–0.7 | 0.0–0.6 | 0.1–0.8 |
PsA | CD | PsA and CD combined | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Placeboa | Ustekinumabb | Placeboc | Ustekinumabd | Placebo | Ustekinumab | |||||||
+CS | −CS | +CS | −CS | +CS | −CS | +CS | −CS | +CS | −CS | +CS | −CS | |
Number of patients treated | 45 | 334 | 141 | 877 | 351 | 592 | 643 | 1106 | 396 | 926 | 784 | 1983 |
Mean weeks of follow-up | 21.17 | 19.73 | 43.71 | 43.35 | 18.86 | 19.27 | 32.69 | 33.00 | 19.12 | 19.44 | 34.67 | 37.58 |
Mean weeks of treatment | 13.76 | 11.72 | 29.84 | 27.30 | 9.46 | 10.10 | 18.32 | 19.07 | 10.02 | 10.72 | 20.39 | 22.71 |
D/C study drug due to AEs [n (%)] | 3 (6.7) | 19 (5.7) | 7 (5.0) | 24 (2.7) | 17 (4.8) | 28 (4.7) | 48 (7.5) | 60 (5.4) | 20 (5.1) | 47 (5.1) | 55 (7.0) | 84 (4.2) |
PYs of follow-up | 18 | 127 | 119 | 731 | 127 | 219 | 404 | 702 | 146 | 346 | 523 | 1,433 |
Event rate/100 PYs | ||||||||||||
AEs | 185.6 | 366.2 | 210.1 | 261.4 | 706.2 | 715.6 | 646.5 | 638.8 | 640.7 | 587.7 | 547.5 | 446.3 |
95% CIe | 128.5–259.4 | 333.7–401.1 | 184.8–237.9 | 249.8–273.4 | 660.8–754.0 | 680.6–751.9 | 621.9–671.7 | 620.3–657.8 | 600.3–683.2 | 562.4–613.8 | 527.7–568.0 | 435.4–457.4 |
SAEs | 10.9 | 14.2 | 7.6 | 9.6 | 47.9 | 41.5 | 39.1 | 33.2 | 43.3 | 31.5 | 32.0 | 21.2 |
95% CIe | 1.3–39.4 | 8.4–22.5 | 3.5–14.4 | 7.5–12.1 | 36.7–61.6 | 33.4–50.9 | 33.2–45.7 | 29.1–37.7 | 33.3–55.4 | 25.9–38.0 | 27.3–37.2 | 18.8–23.7 |
Infectionsf | 49.1 | 110.5 | 52.3 | 82.2 | 157.1 | 138.1 | 135.1 | 133.4 | 143.5 | 128.0 | 116.3 | 107.3 |
95% CIe | 22.5–93.3 | 93.0–130.4 | 40.1–67.1 | 75.8–89.1 | 136.1–180.5 | 123.0–154.6 | 124.0–146.9 | 124.9–142.2 | 124.7–164.4 | 116.4–140.5 | 107.3–125.9 | 102.0–112.8 |
Serious infectionsf | 0.0 | 0.8 | 0.8 | 1.0 | 8.6 | 5.9 | 6.4 | 6.4 | 7.6 | 4.1 | 5.2 | 3.6 |
95% CIe | 0.0–16.4 | 0.0–4.4 | 0.0–4.7 | 0.4–2.0 | 4.3–15.5 | 3.2–10.1 | 4.2–9.4 | 4.7–8.6 | 3.8–13.5 | 2.2–6.8 | 3.4–7.5 | 2.7–4.8 |
Adjudicated serious MACE | 0.0 | 0.8 | 0.8 | 0.7 | 0.0 | 0.0 | 0.0 | 0.1 | 0.0 | 0.3 | 0.2 | 0.4 |
95% CIe | 0.0–16.4 | 0.0–4.4 | 0.0–4.7 | 0.2–1.6 | 0.0–2.4 | 0.0–1.4 | 0.0–0.7 | 0.0–0.8 | 0.0–2.1 | 0.0–1.6 | 0.0–1.1 | 0.2–0.9 |
Deaths | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
95% CIe | 0.0–16.4 | 0.0–2.4 | 0.0–2.5 | 0.0–0.4 | 0.0–2.4 | 0.0–1.4 | 0.0–0.7 | 0.0–0.4 | 0.0–2.1 | 0.0–0.9 | 0.0–0.6 | 0.0–0.2 |
Malignancies (excluding NMSC) | 0.0 | 0.0 | 0.0 | 0.1 | 0.0 | 0.0 | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 0.4 |
95% CIe | 0.0–16.4 | 0.0–2.4 | 0.0–2.5 | 0.0–0.8 | 0.0–2.4 | 0.0–1.4 | 0.0–0.7 | 0.2–1.5 | 0.0–2.1 | 0.0–0.9 | 0.0–0.6 | 0.1–0.8 |
Induction (through week 8) | Maintenance (through week 44) | |||||||
---|---|---|---|---|---|---|---|---|
Placeboa | Ustekinumabb | Placeboa | Ustekinumabb | |||||
+IMM | −IMM | +IMM | −IMM | +IMM | −IMM | +IMM | −IMM | |
Number of patients treated | 195 | 429 | 410 | 952 | 70 | 136 | 112 | 223 |
Mean weeks of follow-up | 8.2 | 8.1 | 8.1 | 8.2 | 27.2 | 24.7 | 33.4 | 30.3 |
Percentage of patients with one or more: | ||||||||
AEs | 56.4 | 66.0 | 57.8 | 62.6 | 77.1 | 81.6 | 72.3 | 79.8 |
SAEs | 8.7 | 5.4 | 3.9 | 5.9 | 11.4 | 11.8 | 9.8 | 9.9 |
Infectionsc | 26.2 | 22.4 | 18.8 | 23.1 | 40.0 | 41.9 | 41.1 | 42.6 |
Deaths | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
3.3 Deaths
3.4 AEs of Special Interest
3.4.1 Opportunistic Infections
3.4.2 Tuberculosis Infection
3.4.3 Serious Major Adverse Cardiovascular Events
3.4.4 Malignancies
Psoriasis | PsA | CD | All patients | |||||
---|---|---|---|---|---|---|---|---|
Comparatora | Ustekinumabb | Placeboc | Ustekinumabd | Placeboe | Ustekinumabf | Comparator | Ustekinumab | |
Number of patients treated | 733 | 3117 | 379 | 1018 | 943 | 1749 | 2055 | 5884 |
NMSC | ||||||||
Total (median) PYs of follow-up | 182 (0.2) | 2558 (0.9) | 145 (0.4) | 849 (1.0) | 346 (0.2) | 1105 (0.6) | 673 (0.2) | 4512 (0.8) |
Patients with event/incidence/100 PYs | 2/1.1 | 24/0.9 | 0/0.0 | 2/0.2 | 2/0.6 | 4/0.4 | 4/0.6 | 30/0.7 |
95% CIg | (0.1–4.0) | (0.6–1.4) | (0.0–2.1) | (0.0–0.9) | (0.1–2.1) | (0.1–0.9) | (0.2–1.5) | (0.5–1.0) |
Malignancies excluding NMSC and in situ cervical cancer | ||||||||
Total (median) PYs of follow-up | 182 (0.2) | 2563 (0.9) | 145 (0.4) | 849 (1.0) | 347 (0.2) | 1106 (0.6) | 674 (0.2) | 4519 (0.8) |
Patients with event/incidence/100 PYs | 1/0.6 | 11/0.4 | 0/0.0 | 1/0.1 | 0/0.0 | 3/0.3 | 1/0.2 | 15/0.3 |
95% CIg | (0.0–3.1) | (0.2–0.8) | (0.0–2.1) | (0.0–0.7) | (0.0–0.9) | (0.1–0.8) | (0.0–0.8) | (0.2–0.6) |
All malignancies | ||||||||
Total (median) PYs of follow-up | 181 (0.2) | 2556 (0.9) | 145 (0.4) | 849 (1.0) | 346 (0.2) | 1105 (0.6) | 673 (0.2) | 4510 (0.8) |
Patients with event/incidence/100 PYs | 3/1.7 | 35/1.4 | 0/0.0 | 3/0.4 | 2/0.6 | 7/0.6 | 5/0.7 | 45/1.0 |
95% CIg | (0.3–4.8) | (1.0–1.9) | (0.0–2.1) | (0.1–1.0) | (0.1–2.1) | (0.3–1.3) | (0.2–1.7) | (0.7–1.3) |
Patients included in SEER analysish | 722 | 3033 | 373 | 1005 | 914 | 1689 | 2009 | 5727 |
Total (median) PYs of follow-up | 179 (0.2) | 2497 (0.9) | 143 (0.5) | 839 (1.0) | 334 (0.2) | 1068 (0.6) | 656 (0.2) | 4403 (0.8) |
Observed/expectedi patients with event | 1/1.0 | 10/13.2 | 0/0.9 | 1/4.9 | 0/1.2 | 2/3.6 | 1/3.0 | 13/21.7 |
SIRj | 1.1 | 0.8 | 0.0 | 0.2 | 0.0 | 0.6 | 0.3 | 0.6 |
SIR 95% CIg | (0.0–5.8) | (0.4–1.4) | (0.0–3.5) | (0.0–1.1) | (0.0–2.6) | (0.1–2.0) | (0.0–1.9) | (0.3–1.0) |