Introduction
The Phase 3 QUASAR Induction Study (NCT04033445) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction therapy in patients (pts) with moderately to severely active ulcerative colitis (UC). Here the early onset of symptom improvement was evaluated.
Aims & Methods
Pts were randomized in a 3:2 ratio to receive IV GUS 200mg or placebo (PBO) at Weeks (Wks) 0, 4, and 8. The primary analysis population included treated pts with a baseline modified Mayo score of 5 to 9, , and an endoscopy subscore ≥ 2 (centrally read). Through Wk12, pts recorded stool production and episodes of rectal bleeding in a diary. Symptomatic remission at Wks 2, 4, and 12 were major secondary endpoints. All other analyses were prespecified but not multiplicity controlled (nominal p-values).
Results
Seven hundred one pts were randomized and treated in the primary analysis population (mean UC duration, 7.5yrs, Mayo endoscopy subscore=3 [severe disease], 67.9%, and mean modified Mayo score, 6.9, at baseline). At baseline, 49.1% had prior inadequate response/intolerance to advanced therapies (ADT-IR) for UC; nearly half of these (47.4%) had ≥2 ADT-IR classes. At baseline, for the GUS and PBO groups, respectively, the mean absolute number of stools per day were 7.10 and 6.96; stool frequency subscores of 0 or 1 were observed in 10.0% and 9.6%; and mean rectal bleeding subscores were 1.7 and 1.8.
As early as Wk2 and increasing through Wk12, greater symptomatic improvements were seen in pts treated with GUS compared with PBO. At Wks 2, 4, 8, and 12, symptomatic response was achieved by GUS- vs PBO-treated pts in 34.0% vs 23.6%, 53.2% vs 30.0%, 66.0% vs 39.6%, and 71.7% vs 35.0% (all p<0.001, except Wk2, p<0.01), respectively. Percentages of pts who achieved symptomatic remission with GUS vs PBO at Wks 2, 4, 8, and 12 were 12.1% vs 9.3%, 22.6% vs 12.9%, 39.7% vs 20.7%, and 49.9% vs 20.7% (all p<0.001, except Wk2, p=0.210), respectively. Mean changes from baseline in absolute number of stools per day at Wks 2, 4, 8 and 12 were -1.19 vs -0.61, -2.05 vs -0.75, -2.75 vs -1.31, and -3.15 vs -1.36 (all p<0.001, except Wk2, p<0.01), respectively. Percentages of pts with stool frequency subscore of 0 or 1 at Wks 2, 4, 8, and 12 were 26.1% vs 18.2%, 41.3% vs 25.4%, 53.4% vs 29.6%, and 60.1% vs 31.8% (all p<0.001, except Wk2, p<0.05), respectively. Mean changes from baseline in rectal bleeding subscores at Wks 2, 4, 8, and 12 were -0.6 vs -0.5, -0.8 vs -0.5, -1.1 vs -0.6, and -1.2 vs -0.6 (all p<0.001, except Wk2, p<0.01), respectively. Percentages of pts with rectal bleeding subscores of 0 at Wks 2, 4, 8, and 12 were 24.2% vs 19.3%, 36.8% vs 22.9%, 55.8% vs 33.2%, and 64.6% vs 28.6% (all p<0.001, except Wk2, p=0.110), respectively. Treatment differences for GUS vs PBO were evident across Wk 12 symptomatic outcomes (Table).
Table 1. Symptomatic outcomes at Wk12
| Placebo IV
| Guselkumab 200 mg IV
| Treatment Difference d (95% CI)
|
Primary analysis population, N
| 280
| 421
| - |
Symptomatic response,a,b
proportion of patients (95% CI)
| 35.0% (29.4%, 40.6%)
| 71.7% (67.4%, 76.0%)
| 37.0% (30.1%, 43.9%)***
|
Symptomatic remission,a,c
proportion of patients (95% CI)
| 20.7% (16.0%, 25.5%)
| 49.9% (45.1%, 54.7%)
| 29.4% (22.8%, 36.0%),
P<0.001
|
Stool frequency subscore of 0 or 1 a
proportion of patients (95% CI)
| 31.8% (26.3%, 37.2%)
| 60.1% (55.4%, 64.8%)
| 28.5% (21.5%, 35.6%)***
|
Rectal bleeding subscore of 0 a
proportion of patients (95% CI)
| 28.6% (23.3%, 33.9%)
| 64.6% (60.0%, 69.2%)
| 36.2% (29.3%, 43.2%)***
|
Absolute number of stools per day,a
mean change from baseline (95% CI)
| N=274
-1.36 (-1.7, -1.0)
| N=420
-3.15 (-3.5, -2.8)
| -1.78 (-2.20, -1.37)***
|
Rectal bleeding subscore,a
mean change from baseline (95% CI)
| N=274
-0.6 (-0.7, -0.5)
| N=420
-1.2 (-1.3, -1.1)
| -0.7 (-0.8, -0.5)***
|
| *** Nominal p<0.001. a Patients who had a prohibited change in UC medication, an ostomy or colectomy, or discontinued study agent due to lack of efficacy or an adverse event of worsening of UC prior to the designated time point were considered not to have achieved the endpoint for binary endpoints and had baseline observation carried forward for continuous endpoints. Data after discontinuation of study agent due to COVID-19 related reasons (excluding COVID-19 infection) were considered to be missing. Patients who were missing one or more components pertaining to a specified endpoint were considered not to have achieved the endpoint for binary endpoints and had baseline observation carried forward for continuous endpoints. The p-values for binary endpoints were based on the Cochran-Mantel-Haenszel (CMH) chi-square test. The p-values for continuous endpoints were based on a Mixed-Effect Model Repeated Measures. b Symptomatic response was defined a decrease from induction baseline in the symptomatic Mayo score (sum of the stool frequency and the rectal bleeding subscores) by ≥ 30% and ≥ 1 point, with either a ≥ 1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. c Symptomatic remission was defined as a stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0. d Treatment differences in proportions were adjusted for strata (ADT-IR status and concomitant use of corticosteroids at baseline) based on Cochran-Mantel-Haenszel weight; treatment differences in change from baseline values were for LS means from a Mixed-effect Model Repeated Measure (MMRM). |
Conclusion
GUS 200mg IV induction was effective in improving symptoms as early as 2 weeks after the first dose in pts with moderately to severely active UC. Symptomatic improvements increased through Wk12.
Disclosure
Gary R. Lichtenstein discloses relationships with Janssen/ Janssen Orthobiotech (Consultant, Research, Funding to University of PA [IBD Fellow Education]). Steering Committee member for Janssen.
Axel Dignass reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Janssen; consultancy fees from Janssen; payment from lectures including service on speakers bureaus from Janssen. Steering Committee member for Janssen.
David T. Rubin has served as a consultant and Steering Committee member to Janssen Pharmaceuticals.
Shadi Yarandi is an employee of Johnson & Johnson and owns company stock/stock options.
Kuan-Hsiang G. Huang is an employee of Johnson & Johnson and owns company stock/stock options.
Matthew Germinaro is an employee of Johnson & Johnson and owns company stock/stock options.
Ye Miao is an employee of Johnson & Johnson and owns company stock/stock options.
Hongyan Zhang is an employee of Johnson & Johnson and owns company stock/stock options.
Jaroslaw Kierkus is a clinical investigator and consultant for Janssen.
Ursula Seidler reports research grants from and is advisor/speaker for Janssen.
Atsuo Maemoto is a clinical investigator and consultant for Janssen.
Jessica R. Allegretti is a consultant and Steering Committee member for Janssen.
Brian Bressler is an advisor/speaker and Steering Committee Member for and has received research support from Janssen.
Laurent Peyrin-Biroulet reports personal fees from Janssen and is a Steering Committee member for Janssen.
