UNIFI
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A Study to Evaluate the Safety and Efficacy of the Ustekinumab Induction and Maintenance Therapy in Participants with Moderately to Severely Active Ulcerative Colitis

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Registro de estudios EU Clinical Trials Register
Año 2015
Enlaces EUCTR - DE EUCTR - HU EUCTR - AT EUCTR - CZ EUCTR - DK EUCTR - NL EUCTR - SK EUCTR - BE EUCTR - BG EUCTR - PL EUCTR - IT
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INTERVENTION: Product Name: Ustekinumab Product Code: CNTO1275 Pharmaceutical Form: Solution for infusion INN or Proposed INN: Ustekinumab CAS Number: 815610‐63‐0 Current Sponsor code: CNTO1275 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 5‐ Pharmaceutical form of the placebo: Solution for infusion Route of administration of the placebo: Intravenous use Trade Name: STELARA® Product Name: Ustekinumab Product Code: CNTO1275 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Ustekinumab CAS Number: 815610‐63‐0 Current Sponsor code: CNTO1275 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 90‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use CONDITION: Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] Ulcerative Colitis ; MedDRA version: 19.0 Level: LLT Classification code 10045365 Term: Ulcerative colitis System Organ Class: 100000004856 PRIMARY OUTCOME: Main Objective: Induction study:; ‐To evaluate the efficacy of IV ustekinumab in inducing clinical remission in subjects with moderately to severely active ulcerative colitis (UC).; ‐To evaluate the safety of IV ustekinumab in subjects with moderately to severely active UC.; ; Maintenance study:; ‐ To evaluate clinical remission for SC maintenance regimens of ustekinumab in subjects with moderately to severely active UC induced into clinical response with ustekinumab.; ‐ To evaluate the safety of SC maintenance regimens of ustekinumab in subjects with moderately to severely active UC induced into clinical response with ustekinumab. Primary end point(s): Induction study:; ‐ Number of Participants With Clinical Remission; ; Maintenance study:; ‐ Number of Participants with Clinical Remission Among Participants in Clinical Response to IV Ustekinumab Induction Treatment Secondary Objective: Induction ; ‐ efficacy of IV ustekinumab in inducing endoscopic healing, clinical response ; ‐ impact of IV ustekinumab on disease‐specific health‐related quality of life; ‐ efficacy of ustekinumab on mucosal healing; ‐ efficacy of induction therapy with IV ustekinumab by biologic failure status; ‐ PK, immunogenicity, and PD of ustekinumab induction therapy ; ; Maintenance ; ‐ efficacy in maintaining clinical response in subjects induced into clinical response with ustekinumab; ‐ endoscopic healing in subjects induced into clinical response ; ‐ efficacy of ustekinumab in achieving corticosteroid‐free clinical remission; ‐ efficacy of ustekinumab in maintaining clinical remission; ‐ efficacy of ustekinumab treatment on mucosal healing ; ‐ impact of SC ustekinumab on disease‐specific health‐related quality of life; ‐ efficacy of maintenance therapy with SC ustekinumab by biologic failure status; ‐ PK, immunogenicity, and PD of ustekinumab maintenance therapy Timepoint(s) of evaluation of this end point: Induction study:; ‐ Week 8 ; ; Maintenance study:; ‐ Week 44 SECONDARY OUTCOME: Secondary end point(s): Induction study: ; 1) Number of Participants with Clinical Response ; 2) Number of Participants With Endoscopic Healing ; 3) Mean Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Score ; ; Maintenance study: ; 1) Participants with Clinical Response Among Participants in Clinical Response to IV Ustekinumab Induction Treatment ; 2) Number of Participants with Endoscopic Healing Among Participants in Clinical Response to IV Ustekinumab Induction Treatment ; 3) Number of Participants with Clinical Remission and not receiving concomitant corticosteroids at Week 44 ; 4) Number of Participants with Clinical Remission Among those who Achieved Clinical Remission at Maintenance Study Baseline Timepoint(s) of evaluation of this end point: Induction study: ; 1‐3) Week 8 ; ; Maintenance study: ; 1‐4) Week 44 ; INCLUSION CRITERIA: ‐ Has a clinical diagnosis of Ulcerative Colitis (UC) at least 3 months before Screening ‐ Has moderately to severely active UC, defined as a Baseline (Week 0) Mayo score of 6 to 12, including a Screening endoscopy subscore of the Mayo score greater than or equal to (>=) 2 as determined by a central reading of the video endoscopy ‐ Have failed biologic therapy, that is, have received treatment with 1 or more tumour necrosis factor (TNF) antagonists or vedolizumab at a dose approved for the treatment of UC, and have a documented history of failure to respond to or tolerate such treatment; OR Be naïve to biologic therapy (TNF antagonists or vedolizumab) or have received biologic therapy but have not demonstrated a history of failure to respond to, or tolerate, a biologic therapy and have a prior or current UC medication history that includes at least 1 of the following: a. Inadequate response to or failure to tolerate current treatment with oral

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A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis

Registro de estudios clinicaltrials.gov
Año 2015
Enlaces Registro de estudios
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The purpose of this study is to evaluate the efficacy and safety of ustekinumab as intravenous (IV: into the vein) infusion in induction study in participants with moderately to severely active Ulcerative Colitis (UC) and as subcutaneous (SC) administration in maintenance study in participants with moderately to severely active Ulcerative Colitis (UC) who have demonstrated a clinical response to Induction treatment with IV ustekinumab.

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Safety and efficacy of ustekinumab induction therapy in patients with moderate to severe ulcerative colitis: results from the phase 3 unifi study

Revista
Año 2018
Enlaces DOI www.cochranelibrary.com
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Introduction: The purpose of this study was to evaluate the safety and efficacy of intravenous (IV) ustekinumab (UST) induction therapy in patients with moderately to severely active ulcerative colitis (UC) who demonstrated an inadequate response to or were unable to tolerate conventional (ie, corticosteroids, immunomodulators) or biologic therapies (ie, 1 or more TNF blockers or vedolizumab). Aims and Methods: UNIFI was a Phase 3 randomized, double‐blind, placebocontrolled study in which patients were randomized 1:1:1 at Week (Wk) 0 to receive a single IV induction dose of UST 130 mg or a dose approximating UST 6mg/kg [ 6mg/kg]: 260mg [weight 55 kg], 390 mg [weight 455 kg and 85 kg], or 520 mg [weight 485 kg]) or placebo (PBO). At Wk 8, patients were evaluated for clinical remission, endoscopic healing, clinical response, change from baseline in the IBDQ score, and mucosal healing (an endpoint that includes both endoscopic healing and histologic healing). Results: Nine hundred sixty‐one patients, of which about 50% had failed biologic therapy and 16.6% had failed both anti‐TNF and vedolizumab, were randomized to treatment in the primary analysis population; 941 patients (98%) completed through Wk 8. Baseline demographics, UC disease characteristics and concomitant UC medications were generally similar among treatment groups. Significantly (p50.001) higher proportions of patients receiving UST IV 130 mg and 6mg/kg achieved clinical remission, endoscopic healing, clinical response, and mucosal healing at Wk 8 and significant improvement from baseline in IBDQ was achieved (Table 1) compared to PBO. Significant (p50.05) decreases in median levels of fecal biomarkers (calprotectin and lactoferrin) were also observed at Wk 8. Similar proportions of patients reported adverse events (41.4%, 50.0%, and 48.0%), serious adverse events (3.7%, 3.1%, and 6.6%), infections (15.9%, 15.3%, and 15.0%) and serious infections (0.6%, 0.3%, and 1.3%) in the UST IV 130mg 6mg/kg and PBO groups, respectively. No malignancies, opportunistic infections or tuberculosis were reported through Wk 8. One death from esophageal varices hemorrhage was reported for a patient with no known history of cirrhosis in the UST 6mg/kg group prior to Wk 8. Conclusion: A single IV dose of UST resulted in significant improvements in clinical, endoscopic and health‐related quality of life outcomes atWk 8 compared to PBO in patients with moderate‐severe UC who had previously failed conventional or biologic therapy. The therapy was well tolerated through induction.

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Early improvement after intravenous ustekinumab induction in patients with ulcerative colitis: Results from the UNIFI induction trial

Revista American Journal of Gastroenterology
Año 2019
Enlaces DOI www.cochranelibrary.com
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INTRODUCTION: The UNIFI induction study evaluated the efficacy and safety of ustekinumab (UST) in patients with moderately to severely active ulcerative colitis (UC) after a single intravenous infusion. In this analysis, we evaluated the rapidity of the onset of the treatment effect. METHODS: Eligible patients were randomly assigned to placebo (PBO) or UST 130 mg or ;6 mg/ kg. Patients recorded stool frequency and categorized rectal bleeding daily for the 7 days before each visit. Partial Mayo scores were calculated at baseline and Week 2 using the average of the stool frequency and rectal bleeding scores from the most recent consecutive 3-day period before the visit and the physician's global assessment score recorded at the visit. C-reactive protein (CRP) and fecal biomarkers were measured at baseline and Day 14. RESULTS: At baseline, the mean 3-day average daily stool frequency was 7.0 in the PBO group, 6.9 in the UST 130-mg group, and 7.0 in the UST ;6-mg/kg group. Patients receiving UST showed greater reductions in the daily number of stools compared with PBO as soon as the first assessment time point at Day 7. Mean changes from baseline in daily stool frequency were -0.7 for PBO, -1.0 for UST 130-mg (P = 0.098), and -1.2 for UST ;6-mg/kg group (P = 0.018) by Day 7, respectively, and -0.9, -1.6 (P < 0.001), and -1.9 (P < 0.001) by Day 13, respectively (Figure 1). Rectal bleeding scores at baseline and Week 2 are summarized in Figure 2. Patients receiving UST showed significantly greater improvement from baseline to Day 14 in partial Mayo score and CRP (Table, P < 0.001 for all comparisons of UST vs PBO). Differences between the UST and PBO treatment groups in mean changes from baseline to Day 14 in fecal calprotectin did not reach significance (PBO -33.96 mg/kg, UST 130 mg 79.12 mg/kg [P = 0.875], UST ;6 mg/kg -412.68 mg/kg [P = 0.152]). However, patients receiving UST showed significantly greater improvement in fecal calprotectin at Week 4 (mean changes from baseline: PBO -226.78 mg/kg, UST 130 mg -881.22 mg/kg [P = 0.013], UST ;6 mg/kg -802.75 mg/kg [P < 0.001]). Similar results were observed for fecal lactoferrin. CONCLUSION: The effect of UST began rapidly after induction, with symptomatic improvement and reduction of systemic inflammation seen as early as the first assessments at Days 7 and 14, respectively. (Figure Presented).

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EFFICACY AND SAFETY OF USTEKINUMAB AS MAINTENANCE THERAPY IN ULCERATIVE COLITIS: WEEK 44 RESULTS FROM UNIFI

Conferencia AGA Abstract Gastroenterology
Año 2019
Enlaces DOI
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Background: The study objective was to evaluate the safety and efficacy of SC ustekinumab (UST) as maintenance therapy in UC patients (pts) who were in clinical response to a single IV induction dose of UST. Methods: This was a Phase 3, double-blind, randomized withdrawal study in pts with moderate-severe active UC who failed conventional or biologic therapy (including anti-TNF and/or vedolizumab) and were in clinical response 8 wks after receiving a single UST IV induction dose. The primary study population included 523 pts randomized 1:1:1 to placebo (PBO) SC, UST 90 mg SC q8w or q12w at Wk 0. The primary endpoint was clinical remission at Wk 44 (52 wks after IV induction); key secondary endpoints were maintenance of clinical response, endoscopic healing, corticosteroid-free clinical remission, and maintenance of clinical remission among pts who achieved clinical remission at baseline. Results: Baseline (induction Wk 0) demographics, UC disease characteristics, concomitant UC medications and medication history were generally similar among treatment groups. Significantly greater proportions of UST q8w and q12w pts were in clinical remission at Wk 44 (43.8% and 38.4%, respectively) vs PBO pts (24.0%; p<0.001 and p=0.002, respectively). Significantly greater proportions of UST q8w and q12w pts maintained clinical response through Wk 44 and achieved endoscopic healing and corticosteroid-free clinical remission vs PBO pts. Clinical remission through Wk 44 was maintained for a significantly greater proportion of q12w pts and a numerically greater proportion of q8w vs PBO pts (Table 1). The proportions of pts with AEs, serious AEs, infections, and serious infections in the UST groups were generally comparable to PBO group. The proportions of pts who discontinued study agent were lower with UST q8w and q12w vs PBO. Among the primary population in the maintenance study: no deaths, 2 malignancies other than NMSC (1 colon cancer, q8w; 1 papillary renal cell carcinoma, q12w) were reported (Table 2). One pt reported NMSC (2 SCC events, q12w). Conclusion: Both UST 90 mg q8w and q12w SC achieved clinical remission and maintained clinical response and were effective in achieving endoscopic healing and corticosteroid-free remission among pts with moderate to severe UC induced into clinical response with single IV dose of UST. The safety for UST in UC pts was consistent with the known safety profile of UST in Crohn's Disease. [Table presented] [Table presented]

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PHARMACOKINETICS AND EXPOSURE-RESPONSE RELATIONSHIPS OF INTRAVENOUSLY ADMINISTERED USTEKINUMAB DURING INDUCTION TREATMENT IN PATIENTS WITH ULCERATIVE COLITIS: RESULTS FROM THE UNIFI INDUCTION STUDY

Revista Gastroenterology
Año 2019
Enlaces DOI www.cochranelibrary.com
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Background: Pharmacokinetic (PK) & exposure-response (ER) data for ustekinumab (UST) from the UNIFI study in ulcerative colitis (UC)1 were evaluated. Methods: PK, efficacy, & safety data were obtained from this Phase 3, double-blind, placebo-controlled induction trial which enrolled 961 pts with moderate-severe UC. Pts who previously failed biologics (1 or more TNF-blockers or vedolizumab) or conventional therapy (corticosteroid and/or 6-MP/AZA) were included. Pts were randomized 1:1:1 to receive an IV induction dose of UST 130mg or a weight-range based dose of ~ 6mg/kg, or placebo at Week 0. Serum UST concentrations & antibodies to UST were evaluated with validated assays. Clinical efficacy outcomes based on the Mayo score were assessed at Wk8; C-reactive protein (CRP) and fecal markers were evaluated as efficacy biomarkers. The relationships between serum UST concentrations & efficacy, as well as the incidence of infections, serious infection & serious adverse events (SAE) during induction were evaluated. Results: Serum UST concentrations over time through Wk8 were dose proportional&similar between biofailure&non-biofailure pts, & pts receiving immunomodulators (IMM) at baseline & those not receiving IMM. Median peak serum UST concentrations for UST 130mg & ~6mg/kg dose groups were 43.2čg/mL & 127.0čg/mL, respectively; median Wk8 UST concentrations were 2.5čg/mL & 8.6čg/mL, respectively. The incidence of antibodies to UST through 8wks was 0.6% based on a drug-tolerant assay. Wk8 serum UST concentrations were positively associated with the proportions of pts achieving clinical response, clinical remission, and endoscopic healing (Figure 1), and inversely related to CRP and fecal calprotectin/lactoferrin levels. Greater proportions of pts in the ~6mg/kg group achieved UST exposures in the upper quartiles of UST exposure associated with higher efficacy. Serum UST concentrations were not associated with the incidence of infections, serious infections or SAEs. Conclusions: Serum UST concentrations were approximately dose-proportional & a positive E-R relationship for efficacy was observed during UST induction treatment in pts with UC. No associations were observed between systemic UST exposure & selected safety events at the IV doses evaluated. These results are consistent with those reported for pts with Crohn's Disease. Reference: 1BE Sands, et al. Safety and Efficacy of Ustekinumab Induction Therapy in Patients with Moderate to Severe Ulcerative Colitis: Results: from the Phase 3 UNIFI Study. Presented at ACG 2018, October 9, 2018, Philadelphia, PA. [Figure presented]

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General health status in patients with moderate to severe ulcerative colitis receiving ustekinumab: results from the Phase III UNIFI induction and maintenance studies

Revista
Año 2019
Enlaces DOI www.cochranelibrary.com
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Background and Aim: The UNIFI studies evaluated the safety and efficacy of ustekinumab (UST) intravenous (IV) induction and subcutaneous (SC) maintenance in patients with moderately to severely active ulcerative colitis (UC). We evaluated patient‐reported outcomes related to general health status in these studies. Methods: In the induction study, eligible patients were randomized to a single IV dose of placebo (PBO) (n = 319), UST 130 mg (n = 320), or UST ∼6 mg/kg (n = 322). Patients who were in clinical response 8 weeks after receiving UST induction were eligible for the maintenance study and were randomized to SC PBO (n = 175), UST 90mg q12w (n = 172), or UST 90mg q8w (n = 176). General health status was assessed using the 36‐item Short‐Form Health Survey (SF‐36) and the visual analog scale of EuroQoL‐5D Health Questionnaire (EQ VAS). SF‐36 measured eight (Table presented) functional areas that were summarized into physical and mental component summary (PCS and MCS, respectively) scores. EQ VAS ranges from 0 to 100. Higher SF‐36 and EQ VAS scores indicate better health status. Results: At baseline of the induction study, mean SF‐36 PCS and MCS scores were below the US general population norm of 50 and were indicative of patients with significantly impaired general health status (Table 1). Eight weeks after IV induction, patients receiving UST reported significantly greater improvements in mean SF‐36 PCS and MCS and EQ VAS scores compared with the PBO group (P < 0.001). Statistically significant differences between UST and PBO were observed for each of the individual subscales of the SF‐36 (P ≤ 0.002). Through Week 44 of the maintenance study, mean SF‐36 PCS scores worsened in the PBO group, were maintained in the UST q12w group, and improved in the UST q8w group (Table 2). Mean SF‐36 MCS score also worsened in the PBO group and was maintained in the UST q12w and q8w groups (P ≤ 0.009). The proportions of patients with clinically meaningful improvements in SF‐36 PCS and MCS (≥ 5 points) and EQ VAS (> 10 points) scores from induction baseline to maintenance Week 44 were significantly greater in the UST groups compared with PBO (P ≤ 0.001). Conclusion: Patients reported significantly greater improvements in general health status after UST IV induction compared with PBO. In patients who responded to UST IV induction, improvements were sustained or increased with 44 weeks of SC UST maintenance therapy.

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General health status in patients with moderate to severe ulcerative colitis receiving ustekinumab: Results from the Phase 3 UNIFI induction and maintenance studies

Revista Journal of Crohn's and Colitis
Año 2019
Enlaces DOI www.cochranelibrary.com
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Background: The UNIFI studies evaluated the safety and efficacy of ustekinumab (UST) intravenous (IV) induction and subcutaneous (SC) maintenance in patients with moderately to severely active ulcerative colitis (UC). We evaluated patient-reported outcomes related to general health status in these studies. Methods: In the induction study, eligible patients were randomised to a single IV dose of placebo (PBO, n = 319), UST 130 mg (n = 320), or UST ∼6 mg/kg (n = 322). Patients who were in clinical response 8 weeks after receiving UST induction were eligible for the maintenance study and were randomised to SC PBO (n = 175), UST 90 mg q12w (n = 172), or UST 90 mg q8w (n = 176). General health status was assessed using the 36-item Short Form Health Survey (SF-36) and the visual analogue scale of EuroQoL-5D Health Questionnaire (EQ VAS). SF-36 measured 8 functional areas that were summarised into physical and mental component summary scores (PCS and MCS). EQ VAS ranges from 0 to 100. Higher SF-36 and EQ VAS scores indicate better health status. Results: At baseline of the induction study, mean SF-36 PCS and MCS scores were below the USA general population norm of 50 and indicative of patients with significantly impaired general health status (Table 1). Eight weeks after IV induction, patients receiving UST reported significantly greater improvements in mean SF-36 PCS and MCS and EQ VAS scores compared with PBO (p < 0.001). Statistically significant differences between UST and PBO were observed for each of the individual subscales of the SF-36 (p ≤ 0.002). Through Week 44 of the maintenance study, mean SF-36 PCS scores worsened in the PBO group, were maintained in the UST q12w group, and improved in the UST q8w group (Table 2). Mean SF-36 MCS also worsened in the PBO group and were maintained in the UST q12w and q8w groups (p ≤ 0.009). The proportions of patients with clinically meaningful improvements in SF-36 PCS and MCS (≥5 points) and EQ VAS ( >10 points) from induction baseline to maintenance Week 44 were significantly greater in the UST groups compared with PBO (p ≤ 0.001). Conclusions: Patients reported significantly greater improvements in general health status after UST IV induction compared with PBO. In patients who responded to UST IV induction, improvements were sustained or increased with 44 weeks of SC UST maintenance therapy. (Table Presented).

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Ustekinumab improved work productivity in patients with moderate to severe ulcerative colitis: Results from the phase 3 UNIFI induction and maintenance studies

Revista American Journal of Gastroenterology
Año 2019
Enlaces DOI www.cochranelibrary.com
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INTRODUCTION: We evaluated the effect of ustekinumab (UST) on work productivity and daily activity in patients with moderate-severe active ulcerative colitis (UC) in the UNIFI induction and maintenance studies. METHODS: In the induction study, patients were randomized to a single intravenous (IV) dose of placebo (PBO, n = 319), UST 130 mg (n = 320), or UST ;6 mg/kg (n = 322). Patients who were in clinical response 8 wks after receiving UST IV induction were eligible for the maintenance study and randomized to subcutaneous (SC) PBO (n = 175), UST 90 mg q12w (n = 172), or UST 90 mg q8w (n = 176). Work productivity was assessed using the Work Productivity and Activity Impairment Questionnaire (WPAI), a validated tool that assesses work time missed (absenteeism), reduced job effectiveness (presenteeism), overall work impairment, and daily activity impairment due to health over the previous week. The impact of UC on overall daily productivity at home, school, and work was assessed using a visual analog scale (VAS, 0 to 10, 0 5 no impact at all, 10 5 impacts very much). RESULTS: At induction baseline, patients had a mean percent work time missed ranging from 17.7% to 19.3%, impairment while working from 39.1% to 45.3%, overall work impairment from 43.7% to 49.1%, and activity impairment from 51.8% to 52.8%. At Wk 8, patients who received UST IV had significantly greater improvement in WPAI domains and daily productivity VAS compared with PBO (Table 1). In the maintenance study, UST-treated patients generally maintained or numerically improved WPAI scores, while scores for patients in the PBO group worsened. The mean changes from baseline toWk 44 in work time missed was 4.7% in the SC PBO group, -2.0% (P = 0.133) in the SC UST 90-mg-q12w group, and 2.1% (P = 0.172) in the SC UST 90-mg-q8w group, impairment while working was 7.4%, 21.6 (P = 0.017), and 26.4% (P < 0.001), respectively; overall work impairment was 7.7%, 22.2% (P = 0.013), and 26.1% (P < 0.001), respectively; and activity impairment was 9.3%, 0.8% (P = 0.002), and 24.2% (P < 0.001), respectively. Mean changes from baseline toWk 44 in daily productivity VAS scores were 1.0, 20.2 (P < 0.001), and 20.5 (P < 0.001), respectively. CONCLUSION: Patients who received UST IV induction reported significantly greater improvement in work productivity and daily activity compared with PBO. In patients who responded to UST IV induction, those who received UST SC maintenance through Wk 44 sustained or improved the levels of work productivity and activity that were achieved during induction. (Figure Presented).

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Efficacy and safety of Ustekinumab as maintenance therapy in ulcerative colitis: Week 44 results from UNIFI

Revista Zeitschrift für Gastroenterologie
Año 2019
Enlaces DOI www.cochranelibrary.com
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Background: Study objective was to evaluate safety and efficacy of SC ustekinumab (UST) as maintenance therapy in UC patients who were in clinical response to a single IV induction dose of UST. Methods: This was a Phase3, double-blind, randomized withdrawal study in patients with moderate-severe UC who failed conventional or biologic therapy (including anti-TNF and/or vedolizumab) and were in clinical response 8 wks after receiving a single UST IV induction dose. Study population included 523 patients randomized 1: 1: 1 to PBO SC, UST90 mg SC q8w or q12w. Primary endpoint was clinical remission at Wk44; key secondary endpoints were maintenance of clinical response, endoscopic healing, corticosteroid-free clinical remission, and maintenance of clinical remission among patients who achieved clinical remission at baseline. Results: Baseline demographics, disease characteristics, concomitant UC medications & medication history were similar among treatments. Significantly greater proportions of UST q8w and q12w patients were in clinical remission at Wk44 (43.8% and 38.4%, respectively) vs. PBO patients (24.0%). Significantly greater proportions of USTq8w and q12w patients maintained clinical response through Wk44 and achieved endoscopic healing and corticosteroid-free clinical remission vs. PBO patients. Clinical remission through Wk44 was maintained for a significantly greater proportion of q12w patients and a numerically greater proportion of q8w vs. PBO patients (Tab. 1). The proportions of patients with AEs, serious AEs, infections, and serious infections with UST were generally comparable to PBO (Tab. 2). (Table Presented) Conclusion: Both UST90 mg q8w and q12w SC achieved clinical remission and maintained clinical response and were effective in achieving endoscopic healing and corticosteroid-free remission among patients with moderate-to-severe UC induced into clinical response with single IV dose of UST. The safety for UST in UC patients was consistent with the known safety profile of UST.

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Molecular response to ustekinumab in moderate-to-severe ulcerative colitis by serum protein and colon transcriptomic analysis: Results from the UNIFI phase 3 maintenance study

Revista American Journal of Gastroenterology
Año 2019
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INTRODUCTION: The cytokines IL-12 and IL-23 are elevated in ulcerative colitis (UC), and genetic association suggests they play causative roles in the disease. Ustekinumab (UST), an anti-IL- 12p40 monoclonal antibody that binds both cytokines, is an effective therapy for moderate-to-severe UC. We previously observed a partial normalization of UC disease signatures in colonic biopsy gene expression and serum protein levels following UST induction therapy. However, the molecular effects of maintenance UST therapy in UC pts are unknown. METHODS: We evaluated the molecular effects of UST in the UNIFI Phase 3 maintenance study of moderate-to-severe UC (n = 961). Pts in response to UST 8 wks after intravenous induction were randomized to maintenance treatment with subcutaneous placebo or UST 90 mg q12w or q8w. Colonic biopsy mRNA and serum samples from the first ;60% of pts treated in the UNIFI phase 3 induction study were analyzed, with equal representation of pts with or without a history of biologic therapy failure (Table 1). Biopsy and serum samples from healthy pts were analyzed as controls. RESULTS: At Wk44 after the start of maintenance therapy, expression of colonic genes dysregulated in UC was altered towards normal levels in all treatment groups, with the greatest improvements among those receiving UST and those in clinical remission (P < 0.05 for Wk 44 versus start of maintenance). No dose effect was observed between q8w and q12w UST doses, and no significant improvements in disease signature occurred in non-responders to placebo or UST. UST maintenance therapy magnified the normalization of serum proteins following UST induction; among pts receiving q8w UST who were in remission at Wk44, the proteins IFNγ, IL-17A, MMP3, and SAA reached concentrations comparable to those seen in healthy controls. Similar trends occurred in pts in remission following q12w UST and to a lesser degree among UST-treated pts not in remission at Wk44. Among pts receiving placebo maintenance therapy who were in remission at Wk 44, the disease-associated serum proteins that decreased following UST induction were not further reduced during maintenance. As previously observed in the induction studies, UST maintenance did not reduce serum TNF levels. CONCLUSION: UST maintenance therapy suppressed IL-12 and IL-23-related serum proteins and promoted normalization of the UC disease transcriptomic profile. These results provide insight into the molecular mechanisms associated with the efficacy of UST maintenance therapy.

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Efficacy in biologic failure and nonbiologic-failure populations in a phase 3 Study of Ustekinumab in moderate-severe ulcerative colitis: UNIFI

Revista Zeitschrift fur Gastroenterologie
Año 2019
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Background: Ustekinumab (UST) was effective in Ph3 induction & maintenance of moderate-severe UC. Efficacy in biologic-failure (BF) and nonbiologic-failure (NBF) populations was evaluated. Methods: Pts were randomized to baseline IV induction UST (130 mg or 6 mg/kg) or PBO. Responders to IV UST induction entered maintenance and were randomized to SC UST90 mg (q12wks or q8wks) or PBO. Primary endpoint for wk8 induction and wk44 maintenance was clinical remission. Major secondary endpoints: wk8 induction = endoscopic healing, clinical response, & change from baseline in total IBDQ score; wk44 maintenance = maintenance of clinical response, endoscopic healing, corticosteroid-free clinical remission, & maintenance of clinical remission in baseline remitters. Results: Among documented BF patients (51.1% of randomized pts), 98.8% failed ≥1 anti-TNF, 32.6% failed both anti-TNF & vedolizumab. NBF pts were predominantly bio-naïve (94.3%). In induction, for BF&NBF pts, proportions of pts who achieved clinical remission was significantly greater for UST6 mg/kg and 130 mg vs. PBO. For BF&NBF pts, major secondary endpoints of clinical response, endoscopic healing & change from baseline in IBDQ were significantly greater for UST6 mg/kg and 130 mg vs. PBO (Table1). Though treatment differences were generally similar between BF&NBF pts, rates were consistently lower for BF pts in each treatment group. In maintenance, for BF&NBF pts, proportions of pts who achieved clinical remission was significantly greater for USTq8w and q12w vs. PBO; proportions of pts who achieved each major secondary endpoint were generally greater for USTq8wk and q12wk vs. PBO (Table2). (Table Presented) Conclusion: UST was effective for induction & maintenance treatment of moderate-severe UC pts with history of biologic failure (ie, TNFantagonists and/or vedolizumab) as well as pts without history of biologic failure.

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Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from the UNIFI study

Revista Journal of gastroenterology and hepatology
Año 2019
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Background and Aim: The study objective was to evaluate the safety and efficacy of subcutaneous (SC) ustekinumab (UST) as maintenance therapy in patients with ulcerative colitis (UC) who were in clinical response to a single intravenous induction dose of UST. Methods: This was a Phase III, double‐blind, randomized withdrawal study in patients with moderate‐severe active UC who failed conventional or biological therapy (including antitumor necrosis factor [TNF] and/or vedolizumab) and were in clinical response 8 weeks after receiving a single UST intravenous induction dose. The primary study population included 523 patients randomly assigned 1:1:1 to placebo (PBO) SC, UST 90 mg SC q8w or q12w at Week 0. The primary endpoint was clinical remission at Week 44 (52 weeks after intravenous induction); key secondary endpoints were maintenance of clinical response, endoscopic healing, corticosteroid‐free clinical remission, and maintenance of clinical remission among patients who achieved clinical remission at baseline. Results: Baseline (induction Week 0) demographics, UC disease characteristics, concomitant UC medications, and medication history were generally similar among treatment groups. Significantly greater proportions of UST q8w and q12w patients were in clinical remission at Week 44 (43.8% and 38.4%, respectively) compared with PBO patients (24.0%; P < 0.001 and P = 0.002, respectively). Significantly greater proportions of UST q8w and q12w patients maintained clinical response through Week 44 and achieved endoscopic healing and corticosteroid‐free clinical remission compared with PBO patients. Clinical remission through Week 44 was maintained for a significantly greater proportion of q12w patients and a numerically greater proportion of q8w versus PBO patients (Table 1). The proportions of patients with adverse events (AEs), serious AEs, infections, and serious infections in the UST groups were generally comparable to those in the PBO group. The proportions of patients who discontinued the study agent were lower with UST q8w and q12w compared with PBO. Among the primary population in the maintenance study, no deaths and two malignancies other than non‐melanoma skin cancer (NMSC) (one colon cancer, q8w; one papillary renal cell carcinoma, q12w) were reported (Table 2). One patient reported NMSC (two squamous cell carcinoma events, q12w). Conclusion: Both UST 90 mg q8w and q12w SC achieved clinical remission and maintained clinical response and were effective in achieving endoscopic healing and corticosteroid‐free remission among patients with moderate to severe UC induced into clinical response with a single intravenous dose of UST. The safety of UST in patients with UC was consistent with the known safety profile of UST in patients with Crohn's disease. (Table presented).

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Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.

Revista The New England journal of medicine
Año 2019
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BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

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Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from UNIFI

Conferencia Journal of Crohn's & colitis
Año 2019
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Background: The study objective was to evaluate the safety and efficacy of SC ustekinumab (UST) as maintenance therapy in UC patients who were in clinical response to a single IV induction dose of UST. Methods: This was a Ph3, double‐blind, randomised withdrawal study in patients with moderate‐severe active UC who failed conventional or biologic therapy (including anti‐TNF and/or vedolizumab) and were in clinical response 8 weeks after receiving a single UST IV induction dose. The primary study population included 523 patients randomised 1:1:1 to placebo (PBO) SC, UST 90 mg SC q8w or q12w at Week 0. Primary endpoint was clinical remission at Week 44 (52 weeks after IV induction); key secondary endpoints were maintenance of clinical response, endoscopic healing, corticosteroid‐free clinical remission, and maintenance of clinical remission among patients who achieved clinical remission at baseline. Results: Baseline (induction Week 0) demographics, UC disease characteristics, concomitant UC medications, and medication history were generally similar among treatment groups. Significantly greater proportions of UST q8w and q12w patients were in clinical remission at Week 44 (43.8% and 38.4%, respectively) vs. PBO patients (24.0%; p < 0.001 and p = 0.002, respectively). Significantly greater proportions of UST q8w and q12w patients maintained clinical response through Week 44 and achieved endoscopic healing and corticosteroid‐free clinical remission vs. PBO patients. Clinical remission through Week 44 was maintained for a significantly greater proportion of q12w patients and a numerically greater proportion of q8w vs. PBO patients. The proportions of patients with AEs, serious AEs, infections, and serious infections in the UST groups were generally comparable to PBO group. The proportions of patients who discontinued study agent were lower with UST q8w and q12w vs. PBO. Among the primary population in the maintenance study: no deaths, 2 malignancies other than NMSC (1 colon cancer,q8w; 1 papillary renal cell carcinoma, q12w) were reported. One patient‐reported NMSC (2 SCC events, q12w). Conclusions: Both UST 90 mg q8w and q12w SC achieved clinical remission and maintained clinical response and were effective in achieving endoscopic healing and corticosteroid‐free remission among patients with moderate‐severe UC induced into clinical response with single IV dose of UST. The safety for UST in UC patients was consistent with the known safety profile of UST in CD. (Figure Presented).

Estudio primario

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Safety of ustekinumab in inflammatory bowel diseases: integrated safety analysis of results from phase 2 and 3 studies in crohn's disease and ulcerative colitis

Revista
Año 2019
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Introduction: Ustekinumab (UST) is a well‐established therapy in Crohn's disease (CD) and psoriatic diseases. Recently presented phase 3 data showed that UST was safe and effective in ulcerative colitis (UC). Phase 3 induction and maintenance studies of UST in CD (UNITI, IMUNITI) and UC (UNIFI) had similar designs, which allows for integrated analysis across both inflammatory bowel disease (IBD) indications. Aims &Methods: We present an analysis of integrated safety data of UST in IBD. Data from 6 phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year of follow‐up. In phase 3, CD and UC pts received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8 or q12 wks). Concomitant immunomodulators (IMM) and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes through 1 year are presented as the number of pts with events per 100 pt‐years (PY) of follow‐up Results: At induction baseline (2370 pts in pooled phase 3 IBD studies), median age was 38.0 years, 46.9% were receiving corticosteroids, 30.8% were receiving IMM, 53.0% had failed biologics, and 37.1% were naive to biologics. In phase 3 IBD studies, through Wk8 of PBO‐controlled induction, 1582 pts were treated with UST. Pts with ≥1 event (PBO vs UST) were 55.8% vs 53.9% with AEs, 6.2% vs 4.4% with SAEs, 19.9% vs 19.3% with infections, and 1.3% vs 1.1% with serious infections. Through 1 year in pooled phase 2/3 IBD studies, 2574 pts were treated with UST with 1733 PY. The number of patients per 100 PY with AEs (PBO 165.99 vs UST 118.32), SAEs (27.50 vs 21.23), infections (80.31 vs 64.32), serious infections (5.53 vs 5.02), malignancies including non‐melanoma skin cancer (NMSC) (0.50 vs 0.81), and discontinuations of study agent because of an AE (13.41 vs 7.73) were similar between UST and PBO. The most frequently occurring AEs (excluding diseases under study) were arthralgia (PBO 16.93 vs UST 16.56), headache (16.43 vs 16.50), nausea (13.25 vs 11.94), and abdominal pain (14.59 vs 11.54), and infections were nasopharyngitis (16.26 vs 18.11) and upper respiratory tract infection (11.40 vs 11.36). Results were similar for the CD and UC studies separately (Table shows key safety events). (Table Presented) [Number of pts with key safety events through 1 year of treatment per 100 PY of follow‐up (number of patients with events) in phase 2/3 CD &UC studies] Regarding serious infections, the CD‐specific manifestation of anal abscess occurred in PBO 2.02 and UST 0.90 pts per 100 PY in CD pts. When CD‐specific events were excluded, overall rates of serious infections were similar between UC and CD populations. In pooled phase 2/3 studies, the only malignancy (excluding NMSC) reported in >1 UST‐treated pt was prostate cancer; no lymphomas were reported through 1 year. Two pts receiving UST (0.12 per 100 PY; both had UC) died from events that investigators considered to be unrelated to study agent (esophageal varices hemorrhage and acute respiratory failure during thyroid surgery). Conclusion: The safety profile of UST in pts with UC and across integrated IBD indications through 1 year was favorable and consistent with the established safety profile in pts with CD and psoriatic disease.

Estudio primario

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Sustained remission in patients with moderate to severe ulcerative colitis: Results from the phase 3 UNIFI maintenance study

Revista Zeitschrift fur Gastroenterologie
Año 2019
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Background: The UNIFI randomized-withdrawal maintenance study evaluated the safety and efficacy of subcutaneous (SC) ustekinumab in patients with moderately-to-severely active ulcerative colitis (UC) who had responded to intravenous (IV) ustekinumab during induction. In this analysis, durability of remission through maintenance Week44 is described. Methods: At Week0 of the maintenance study, 523 patients who had responded to IV ustekinumab induction were randomized 1 : 1 : 1 to placebo SC, ustekinumab SC 90 mg q12w, or ustekinumab SC 90 mg q8w. Maintenance of clinical remission at Week44 was a major secondary endpoint; partial Mayo scores, rectal bleeding and stool frequency Mayo subscores, endoscopic healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) scores were also assessed. Results: At baseline of the maintenance study, proportions of patients in symptomatic remission and IBDQ remission were similar among treatment groups (Tab. 1). The proportion of patients with endoscopic healing at baseline was lower in the ustekinumab q8w group (32.4%) compared with ustekinumab q12w (39.5%) and placebo groups (40.6%). Through Week 44, the proportions of patients in partial Mayo remission were sustained in the ustekinumab treatment groups, while the proportion of patients in the placebo group decreased, with consistent numerical separation from the ustekinumab q8w group by Week 8 and the q12w group by Week 16. Significantly greater proportions of patients in both ustekinumab groups compared with placebo maintained symptomatic and IBDQ remission through Week 44 and maintained endoscopic healing at Week 44 among patients who achieved each respective endpoint at maintenance baseline. Similarly, greater proportions of ustekinumab-treated patients had durable partial Mayo remission through Week44 versus placebo. (Table Presented) Conclusion: Both doses of ustekinumab SC maintenance therapy sustained remission, measured by patient-reported symptoms and endoscopic and quality of life assessments, in patients with moderately-to-severely active UC.

Estudio primario

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Effects of ustekinumab maintenance therapy on endoscopic improvement and histologic improvement in the UNIFI phase 3 study in ulcerative colitis

Revista American Journal of Gastroenterology
Año 2019
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INTRODUCTION: Ustekinumab (UST) is an effective therapy for moderate-to-severe ulcerative colitis (UC), but its effects on mucosal healing (endoscopic improvement 1 histologic improvement) during maintenance treatment are unknown. METHODS: We evaluated the effects of maintenance UST on histologic and endoscopic activity in the UNIFI Phase 3 study of UST in moderate-to-severe UC (n = 961). Pts in response 8 weeks after receiving intravenous UST were randomized to receive maintenance treatment with subcutaneous (SC) placebo or UST 90 mg every 8 (q8w) or 12 weeks (q12w). Two colonic biopsies were collected from the distal colon at screening and Weeks 0 and 44 of maintenance. Endoscopic improvement (EI) was defined as a Mayo endoscopy subscore <1; histologic improvement (HI) comprised the following Geboes score-based criteria: absence of erosions or ulcerations, absence of crypt destruction, and <5% of crypts with neutrophil infiltration. To encompass both macroand microscopic scales, histo-endoscopic mucosal healing (MH) was defined as achieving both EI and HI. RESULTS: At maintenance Week 44, EI was achieved in 28.6%, 43.6%, and 51.1% of pts treated with placebo, UST q12w (P = 0.002 vs placebo), and UST q8w (P < 0.001), respectively. HI was achieved at Week 44 in 32.9%, 54.0%, and 59.3% of pts treated with placebo, UST q12w, and UST q8w, respectively (P < 0.001 for both q12w and q8w). MH was achieved at Week 44 in 24.1%, 38.8%, and 45.9% of pts treated with placebo, UST q12w (P = 0.002), and UST q8w (P 0.001), respectively. HI at Week 44 (irrespective of maintenance treatment) was significantly associated with EI and MH (P < 0.001) and with both lower absolute levels and larger post-treatment changes in total Mayo score, partial Mayo score, and Mayo symptom sub-scores for stool frequency and rectal bleeding at Week 44. Both EI and HI following 8 weeks of UST treatment were associated with clinical remission and steroid-free clinical remission at Week 44 (P < 0.05), as well as remission through Week 44 (i.e., at both Week 8 and Week 44). For example, 26% of pts with induction HI were in clinical remission through Week 44, versus 4% of pts without induction HI. Induction MH was similarly associated with positive outcomes at maintenance Week 44. CONCLUSION: Among pts with moderately-to-severely active UC, those receiving SC UST maintenance had higher rates of EI, HI, and MH than those receiving placebo. Both EI and HI are associated with subsequent clinical remission and steroid-free clinical remission. (Figure Presented).

Estudio primario

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Clinical remission by legacy vs. FDA definitions: Definition justification and results from UNIFI Study

Revista Journal of Crohn's and Colitis
Año 2019
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Background: Ustekinumab (UST), an interleukin-12/23 blocker, was evaluated as induction and maintenance for moderate-severe ulcerative colitis (UC). Clinical remission was analysed using a US-specific definition (FDA) excluding the PGA (Physician's Global Assessment) and the legacy definition which includes the PGA to accommo Da te regional regulatory preference. Methods: Patients (pts) were randomised to receive a UST intravenous (IV) induction dose (either 130 mg [n = 320] or approximating 6 mg/kg [n = 322]), or PBO (n = 319). Responders to UST IV induction were randomised to SC maintenance of 90 mg UST (either every 12 weeks [n = 172] or every 8 weeks [n = 176]), or PBO (n = 175). The primary endpoint for induction (Week 8) and maintenance (Week 44) was clinical remission. In a prior UC induction study with golimumab, 87.5% had >3 stools per Da y at baseline and stool number ≤3 aligned with what approximately 98% of patients reported as normal. FDA clinical remission definition was developed after FDA requested PGA removal (ie, absolute stool number ≤3 [aligned with upper limit of normal stool number in the general population], Mayo rectal bleeding subscore 0, and Mayo endoscopy subscore 0/1). This differed from the legacy definition (total Mayo score ≤2 points, with no individual subscore >1). Using golimumab and infliximab UC study Da ta, FDA definition was assessed for agreement with legacy definition, treatment effect, and clinical meaningfulness using the Inflammatory Bowel Disease Questionnaire and the 36-item short form health survey as anchor variables. UNIFI remission was analysed using both definitions. Results: The FDA definition demonstrated high concor Da nce, specificity and sensitivity with the legacy definition with a similar treatment effect, and defined patients who had clinically meaningful benefit. In the UNIFI study, Week 8 clinical remission rates among patients receiving IV UST at either 130 mg or ∼6 mg/kg were significantly higher than PBO patients by both legacy (15.6%, 15.5%, and 5.3%, respectively p < 0.001 for both doses) and FDA definitions (16.6%, 18.9%, and 6.3%, respectively; p < 0.001 for both doses). Week 44 clinical remission rates among patients randomised to q12wk or q8wk UST were significantly higher than PBO patients by both legacy (38.4%, 43.8%, and 24.0%, respectively; p = 0.002 q12wk and p < 0.001 q8wk) and FDA definitions (39.5%, 42.6%, and 24.6% respectively; p = 0.002 q12wk and p < 0.001 q8wk). Conclusions: Using either legacy or FDA remission definition, IV UST induced remission and SC UST maintained remission in UST induction responders with moderately-to-severely active UC. Importantly, the FDA definition with absolute stool number ≤3 is clinically meaningful, easily understood by physicians and patients, and is not based on patients' distant recall of normal stool pattern.

Estudio primario

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USTEKINUMAB THERAPY INDUCED CLINICALLY MEANINGFUL IMPROVEMENT AND REMISSION AS MEASURED BY THE INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 3 UNIFI INDUCTION AND MAINTENANCE STUDIES

Revista Gastroenterology
Año 2019
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Background: The UNIFI studies evaluated the safety and efficacy of ustekinumab (UST) intravenous (IV) induction and subcutaneous (SC) maintenance in patients with moderately to severely active ulcerative colitis (UC). Here, we present patient-reported outcomes from the Inflammatory Bowel Disease Questionnaire (IBDQ). Methods: In the induction study, eligible patients were randomized to a single IV dose of placebo (PBO, n=319), UST 130 mg (n=320), or UST ~6 mg/kg (n=322). Patients who were in clinical response 8 weeks after receiving UST induction were eligible for the maintenance study and were randomized to SC PBO (n=175), UST 90 mg q12w (n=172), or UST 90 mg q8w (n=176). The IBDQ is a 32-item questionnaire with 4 dimensions: bowel symptoms, systemic symptoms, emotional function, and social function. The total score ranges from 32 to 224, higher scores indicate better quality of life, a score ≥170 indicates remission, and a change ≥16 or >20 points was defined as clinically meaningful. Results: Mean total IBDQ scores at induction baseline ranged from 126.0 to 127.4 and were comparable across treatment groups (Table 1). Eight weeks after IV induction, patients receiving UST reported significantly greater improvement in mean IBDQ scores, and greater proportions of patients achieved clinically meaningful improvements from baseline and IBDQ remission compared with PBO (p<0.001 for all comparisons of UST vs PBO). Through 44 weeks of the maintenance study, mean IBDQ scores worsened in the PBO group, were maintained in the UST q12w group, and improved in the UST q8w group (Table 2, p<0.001). Significantly greater percentages of patients in the UST groups achieved or maintained clinically meaningful improvement (p<0.01) or IBDQ remission (p<0.02) through Week 44 compared with PBO. Patients receiving UST induction showed greater improvement in each of four domain scores of the IBDQ at Week 8 compared with PBO, and the improvements were sustained through 44 weeks of maintenance. Conclusion: Patients reported significantly greater improvements in IBDQ scores with UST IV induction compared with PBO. In patients who responded to UST IV induction, significantly greater proportions of patients who received UST SC maintenance sustained the improvements achieved during induction through Week 44, including remission, compared with PBO. [Table Presented] [Table Presented]

Estudio primario

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Efficacy and safety of ustekinumab through Week 16 in patients with moderate-to-severe ulcerative colitis randomised to ustekinumab: results from the UNIFI induction trial

Revista Journal of Crohn's and Colitis
Año 2019
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Background: The objective was to evaluate the efficacy and safety of ustekinumab (UST) through Week 16 induction among patients with moderate‐severe UC randomised to UST in the UNIFI Phase 3 clinical trial. Week 8 induction data have been previously reported.1 Methods: Rates of overall clinical response and clinical remission among blinded patients randomised to IV UST induction were used to evaluate efficacy through Week 16. The number of patients who achieved each endpoint included patients who achieved the endpoint at Week 8 after initial IV UST induction and patients who achieved the same endpoint at Week 16 following a blinded dose of UST 90 mg SC at Week 8 if they were not in clinical response at Week 8. Results: Among patients randomised to UST at Week 0, 77.6% achieved clinical response within 16 weeks: 56.5% at Week 8 after IV induction and an additional 21.1% at Week 16 after receiving UST SC at Week 8. Among the Week 8 non‐responders to UST IV induction who received UST SC at Week 8, 57.9% achieved clinical response at Week 16. Among patients randomised to UST at Week 0, 18.8% achieved clinical remission within 16 weeks: 15.6% at Week 8 after IV induction and an additional 3.2% at Week 16 after receiving an additional UST dose at Week 8. Among the Week 8 non‐responders to UST IV induction who received UST SC at Week 8, 9.4% achieved clinical remission at Week 16. The proportions of patients who achieved clinical response within 16 weeks was lower for patients with a history of biological failure compared with nonbiological failure patients: 70.6% vs. 84.9% (Table 1). Similarly, the proportions of patients who achieved clinical remission during induction within 16 weeks were lower for biological failure patients compared with non‐biological failure patients: 13.3% vs. 24.7% (Table 2). The AE profile for patients who received a single UST IV dose and those with an additional UST dose SC at Week 8 were similar and consistent with the AE profile for patients that received PBO. Conclusions: UST is safe and effective induction therapy in patients with moderate‐severe UC. Similar to results from the Crohn's disease programme, these data support a clinical rationale for continuing treatment with UST through at least one SC dose 8 weeks after IV induction in patients with moderate‐severe UC. (Table Presented).

Estudio primario

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Pharmacokinetics and exposure-response relationships of ustekinumab in patients with ulcerative colitis: Results from the UNIFI induction and maintenance studies

Revista American Journal of Gastroenterology
Año 2019
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INTRODUCTION: Serum concentrations of monoclonal antibody-based biologics have been shown to correlate with their efficacy. PK, exposure-response (ER), and immunogenicity of ustekinumab (UST) were evaluated in UNIFI induction and maintenance studies in UC. Induction results were presented previously. METHODS: PK, immunogenicity, efficacy & safety data were obtained from induction and maintenance Phase 3, double-blind, PBO-controlled trials in adults with moderate-severe UC. Pts (n = 961) in the induction study received a single IV infusion at Wk0 of PBO, UST 130 mg, or UST ∼6 mg/kg UST. Responders to a single IV infusion of UST (n = 523) were randomly assigned to receive SC PBO, UST 90 mg q12w, or UST 90 mg q8w. Blood samples were collected to measure serum UST concentration and antibodies to ustekinumab. Relationships between serum UST concentrations & efficacy measures, and safety outcomes were evaluated. RESULTS: Serum UST concentrations over time were dose proportional, unaffected by concomitant immunosuppressants, & similar between pts who were biologic failures & non-failures. Median peak serum UST concentrations in the induction study were 43.2 μg/mL & 127.0 μg/mL for the 130 mg & ∼6 mg/kg dose groups, respectively. At induction Wk8, median UST concentrations were 2.51 mg/ mL & 8.59 μg/mL, respectively. Steady-state was reached by the start of the second SC maintenance dose. Median steady-state trough serum UST concentrations over time in the UST q8w group (2.69 to 3.09 μg/mL) were 3-fold higher than in the q12w group (0.92 to 1.19 μg/mL). Serum UST concentrations were positively associated with response & remission rates (Table 1), and there was an inverse association between serum UST concentrations and CRP and fecal calprotectin levels. No relationship was observed between serum UST concentrations & the incidence of infections, serious infections or SAEs during induction or maintenance. 3.4% of pts receiving UST maintenance had antibodies to UST through 1 year using a drug-tolerant assay vs. 9.1% with PBO; no impact of antibodies on efficacy was observed. CONCLUSION: Serum UST concentrations were approx. dose-proportional. A positive ER of serum UST with clinical efficacy measures and an inverse relationship with inflammatory markers was observed during UST IV induction & SC maintenance. Adverse events including infections did not increase with increased serum UST concentrations. These findings are consistent with those in UST for Crohn's disease.

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GENERAL HEALTH STATUS IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS RECEIVING USTEKINUMAB: RESULTS FROM THE PHASE 3 UNIFI INDUCTION AND MAINTENANCE STUDIES

Revista Gastroenterology
Año 2019
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Background: The UNIFI studies evaluated the safety and efficacy of ustekinumab (UST) intravenous (IV) induction and subcutaneous (SC) maintenance in patients with moderately to severely active ulcerative colitis (UC). We evaluated patient-reported outcomes related to general health status in these studies. Methods: In the induction study, eligible patients were randomized to a single IV dose of placebo (PBO, n=319), UST 130 mg (n=320), or UST ~6 mg/kg (n=322). Patients who were in clinical response 8 weeks after receiving UST induction were eligible for the maintenance study and were randomized to SC PBO (n=175), UST 90 mg q12w (n=172), or UST 90 mg q8w (n=176). General health status was assessed using the 36-item Short Form Health Survey (SF-36) and the visual analog scale of EuroQoL-5D Health Questionnaire (EQ VAS). SF-36 measured 8 functional areas that were summarized into physical and mental component summary scores (PCS and MCS). EQ VAS ranges from 0-100. Higher SF-36 and EQ VAS scores indicate better health status. Results: At baseline of the induction study, mean SF-36 PCS and MCS scores were below the United States general population norm of 50 and indicative of patients with significantly impaired general health status (Table 1). Eight weeks after IV induction, patients receiving UST reported significantly greater improvements in mean SF-36 PCS and MCS and EQ VAS scores compared with PBO (p<0.001). Statistically significant differences between UST and PBO were observed for each of the individual subscales of the SF-36 (p≤0.002). Through Week 44 of the maintenance study, mean SF-36 PCS scores worsened in the PBO group, were maintained in the UST q12w group, and improved in the UST q8w group (Table 2). Mean SF-36 MCS also worsened in the PBO group and were maintained in the UST q12w and q8w groups (p≤0.009). The proportions of patients with clinically meaningful improvements in SF-36 PCS and MCS (≥5 points) and EQ VAS (>10 points) from induction baseline to maintenance Week 44 were significantly greater in the UST groups compared with PBO (p≤0.001). Conclusion: Patients reported significantly greater improvements in general health status after UST IV induction compared with PBO. In patients who responded to UST IV induction, improvements were sustained or increased with 44 weeks of SC UST maintenance therapy. [Table presented] [Table presented]

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EFFICACY IN BIOLOGIC-FAILURE AND NONBIOLOGIC-FAILURE POPULATIONS IN A PHASE 3 STUDY OF USTEKINUMAB IN MODERATE-SEVERE ULCERATIVE COLITIS: UNIFI

Revista Gastroenterology
Año 2019
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Background: Ustekinumab (UST), an IL12/23 blocker approved for Crohn's disease, was effective in Ph3 induction and maintenance of moderate-severe ulcerative colitis (UC). Efficacy in biologic-failure (BF) and nonbiologic-failure (NBF) populations was evaluated. Methods: Pts were randomized to a baseline intravenous (IV) induction UST dose (130mg or weight-range based doses approximating 6mg/kg (~6mg/kg)), or PBO. Responders to UST IV induction entered maintenance and were randomized to SC 90mg UST (q12wks or q8wks), or PBO. Primary endpoint for wk8 induction and wk44 maintenance was clinical remission. Major secondary endpoints for wk8 induction: endoscopic healing, clinical response, and change from baseline in total IBDQ score and wk44 maintenance: maintenance of clinical response, endoscopic healing, corticosteroid-free clinical remission, and maintenance of clinical remission in baseline remitters. Results: Among pts with documented BF (51.1% of randomized pts), 98.8 % had failed at least 1 anti-TNF, 32.6% had failed both anti-TNF and vedolizumab. NBF pts were predominantly bio-naïve (94.3%). In induction, for BF and NBF pts, proportions of pts who achieved clinical remission was significantly greater for UST ~6mg/kg and 130mg vs PBO (BF pts-P<0.001 for both doses; NBF pts-P<0.05 for both doses, respectively, Table 1). For BF and NBF pts, major secondary endpoints of clinical response and endoscopic healing and change from baseline in IBDQ were significantly greater for UST ~6mg/kg and 130mg vs PBO (Table 1). Though treatment differences were generally similar between BF and NBF pts, rates were consistently lower for BF pts in each treatment group. In maintenance, for BF and NBF pts, proportions of pts who achieved clinical remission was significantly greater for UST q8w and q12w vs PBO (BF pts- P<0.001, P=0.044, respectively; NBF pts- P=0.024, P=0.020, respectively, Table 2). For BF and NBF pts, proportions of pts who achieved each major secondary endpoint was generally greater for UST q8wk and q12wk vs PBO. In BF pts, the efficacy of UST q8wk was generally greater than UST q12wk (Table 2). Conclusion: UST was effective for induction and maintenance treatment of moderate-severe UC pts with a history of biologic therapy failure (ie TNF-antagonists and/or vedolizumab) as well as pts without a history of biologic therapy failure who were predominantly bio-naive. [Table Presented] [Table Presented]

Estudio primario

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Corticosteroid sparing effects of ustekinumab therapy in uc patients: Results from the UNIFI program

Revista American Journal of Gastroenterology
Año 2019
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INTRODUCTION: Ustekinumab (UST), an IL12/23 blocker approved for Crohn's disease, was effective in Phase 3 induction and maintenance studies of patients with moderate-severe ulcerative colitis (UC). Since discontinuation of corticosteroids (CS) is an important goal of therapy in UC, this analysis aims to further describe the CS sparing effects of ustekinumab treatment through Week 44 of the UNIFI trial. METHODS: Responders to UST IV induction entered maintenance and were randomized to UST 90 mg SC (q12wks or q8wks), or PBO. During the induction and maintenance studies, oral CS were not to be initiated or increased beyond baseline. At Week 0 of the maintenance study, a scheduled taper was recommended for all patients receiving CS. CS-free Clinical Response (CSR) and remission (CSRem) rates (at Week 44, and for >90 days prior toWeek 44) were calculated for the overall population and for the subset of patients on CS at maintenance baseline. Among the subset of patients on CS at maintenance baseline, the mean prednisone-equivalent (P.Eq) CS dose (mg/day) through Week 44 were calculated as were the rates of subjects who were CS-free at Week 44 and for >90 days prior to Week 44. RESULTS: Overall 50.6% (265/523) of patients in the primary analysis population were receiving CS at maintenance baseline. The proportions of patients who were receiving concomitant CS at maintenance baseline were 52.3%, 47.7%, and 52.3% in the UST q8w, UST q12w and PBO groups, respectively. As detailed in Table 1, in the overall population, CSR and CSRem rates were significantly higher for patients who continued on UST therapy during maintenance compared with placebo. Among the patients who achieved CSR or CSRem at Week 44, the majority achieved these endpoints and eliminated CS use at or up to 90 days prior to Week 44. Similar results were observed in the subset of patients on concomitant CS at maintenance BL. In this group, the mean daily P.Eq CS dose at maintenance BL was approximately 15.0 mg/day for all treatment groups. Mean decrease in average daily P.Eq dose atWk 44 was more pronounced and the proportion of patients who were CSfree was greater in the UST maintenance arms. CONCLUSION: UST maintenance therapy, with both q8w and q12w dosing regimens, is effective in reducing and eliminating the use of CS in patients with UC; the majority of patients >90%) who achieved clinical response or clinical remission were able to eliminate corticosteroids. (Figure Presented).

Estudio primario

No clasificado

Efficacy in biologic failure and non-biologicfailure populations in a Phase 3 study of ustekinumab in moderate-severe ulcerative colitis: UNIFI

Revista Journal of Crohn's and Colitis
Año 2019
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Background: Ustekinumab (UST), an IL12/23 blocker approved for Crohn's disease, was effective in Ph3 induction and maintenance of moderate-severe ulcerative colitis (UC). Efficacy in biologic-failure (BF) and non-biologic-failure (NBF) populations was evaluated. Methods: Pts were randomised to a baseline IV induction UST dose (130 mg or weight-range based doses approximating 6 mg/kg (∼6 mg/kg)), or PBO. Responders to UST IV induction entered maintenance and were randomised to SC 90 mg UST (q12wks or q8wks), or PBO. Primary endpoint for wk8 induction and wk44 maintenance was clinical remission. Major secondary endpoints for wk8 induction: endoscopic healing, clinical response, and change from baseline in total IBDQ score and wk44 maintenance: maintenance of clinical response, endoscopic healing, corticosteroid-free clinical remission, and maintenance of clinical remission in baseline remitters. Results: Among patients with documented BF (51.1% of randomised patients), 98.8% had failed at least 1 anti-TNF, 32.6% had failed both anti-TNF and vedolizumab. NBF patients were predominantly bio-naïve (94.3%). In induction, for BF and NBF patients, proportions of patients who achieved clinical remission was significantly greater for UST ∼6 mg/kg and 130 mg vs. PBO (BF patientsp < 0.001 for both doses; NBF patients-p < 0.05 for both doses, respectively, Table 1). For BF and NBF patients, major secondary endpoints of clinical response and endoscopic healing and change from baseline in IBDQ were significantly greater for UST ∼6 mg/kg and 130 mg vs. PBO (Table 1). Though treatment differences were generally similar between BF and NBF patients, rates were consistently lower for BF patients in each treatment group. In maintenance, for BF and NBF patients, proportions of patients who achieved clinical remission was significantly greater for UST q8w and q12w vs. PBO (BF patients-p < 0.001, p = 0.044, respectively; NBF patients-p = 0.024, p = 0.020, respectively, Table 2). For BF and NBF patients, proportions of patients who achieved each major secondary endpoint was generally greater for UST q8wk and q12wk vs. PBO. In BF patients, the efficacy of UST q8wk was generally greater than UST q12wk (Table 2). Conclusions: UST was effective for induction and maintenance treatment of moderate-severe UC patients with a history of biologic therapy failure (ie, TNF-antagonists and/or vedolizumab) as well as patients without a history of biologic therapy failure who were predominantly bio-naive. (Table Presented).

Estudio primario

No clasificado

Ustekinumab therapy induced clinically meaningful improvement and remission as measured by the Inflammatory Bowel Disease Questionnaire: Results from the phase 3 UNIFI induction and maintenance studies

Revista Journal of Crohn's and Colitis
Año 2019
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Background: The UNIFI studies evaluated the safety and efficacy of ustekinumab (UST) intravenous (IV) induction and subcutaneous (SC) maintenance in patients with moderately to severely active ulcerative colitis (UC). Here, we present patient-reported outcomes from the Inflammatory Bowel Disease Questionnaire (IBDQ). Methods: In the induction study, eligible patients were randomised to a single IV dose of placebo (PBO, n = 319), UST 130 mg (n = 320), or UST ∼6 mg/kg (n = 322). Patients who were in clinical response 8 weeks after receiving UST induction were eligible for the maintenance study and were randomised to SC PBO (n = 175), UST 90 mg q12w (n = 172), or UST 90 mg q8w (n = 176). The IBDQ is a 32-item questionnaire with 4 dimensions: bowel symptoms, systemic symptoms, emotional function, and social function. The total score ranges from 32 to 224, higher scores indicate better quality of life, a score ≥170 indicates remission, and a change ≥16 or >20 points was defined as clinically meaningful. Results: Mean total IBDQ scores at induction baseline ranged from 126.0 to 127.4 and were comparable across treatment groups (Table 1). Table 1. Total Inflammatory Bowel Disease Questionnaire (IBDQ) scores through Week 8 in patients who received IV induction treatment with ustekinumab or placebo. Eight weeks after IV induction, patients receiving UST reported significantly greater improvement in mean IBDQ scores, and greater proportions of patients achieved clinically meaningful improvements from baseline and IBDQ remission compared with PBO (p < 0.001 for all comparisons of UST vs. PBO). Through 44 weeks of the maintenance study, mean IBDQ scores worsened in the PBO group, were maintained in the UST q12w group, and improved in the UST q8w group (Table 2, p < 0.001). Table 2: Total Inflammatory Bowel Disease Questionnaire (IBDQ) scores through Week 44 in patients who received SC maintenance treatment with ustekinumab or placebo Significantly greater percentages of patients in the UST groups achieved or maintained clinically meaningful improvement (p < 0.01) or IBDQ remission (p < 0.02) through Week 44 compared with PBO. Patients receiving UST induction showed greater improvement in each of four domain scores of the IBDQ at Week 8 compared with PBO, and the improvements were sustained through 44 weeks of maintenance. Conclusions: Patients reported significantly greater improvements in IBDQ scores with UST IV induction compared with PBO. In patients who responded to UST IV induction, significantly greater proportions of patients who received UST SC maintenance sustained the improvements achieved during induction through Week 44, including remission, compared with PBO. (Table Presented) .

Estudio primario

No clasificado

Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from UNIFI

Conferencia 14th Congress of ECCO
Año 2019
Enlaces 14th Congress of ECCO
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Safety of ustekinumab in inflammatory bowel diseases: Integrated safety analysis of results from phase 2 and 3 studies in Crohn's disease and ulcerative colitis

Revista American journal of gastroenterology
Año 2019
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INTRODUCTION: Ustekinumab (UST) is a well-established therapy in Crohn's disease (CD) and psoriatic diseases. UST was safe and effective in phase 3 ulcerative colitis (UC) studies. Pivotal studies of UST in CD (UNITI, IMUNITI) and UC (UNIFI) had similar designs, which allows for integrated analysis across both indications. We present an integrated safety analysis of UST in inflammatory bowel disease (IBD). METHODS: Data from 6 phase 2/3 studies were pooled, and safety was evaluated through 1 year of follow-up. In phase 3, pts received a single IV placebo (PBO) or UST (130 mg or ∼6 mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90 mg q8w or q12w). Concomitant immunomodulators (IMM) and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes through 1 year are presented as the number of pts with events per 100 patient-years (PY) of follow-up. RESULTS: At induction baseline (2370 pts in pooled phase 3 IBD studies), median age was 38.0 years, 46.9% were receiving corticosteroids, 30.8% were receiving IMM, 53.0% had failed biologics, and 37.1% were naïve to biologics. In phase 3 IBD studies, through Wk8 of PBOcontrolled induction, the frequency of key safety events was similar between UST and PBO (Table 1). In addition, through 1 year across phase 2/3 IBD studies (Table 2), numbers of pts per 100 PY with key safety events were similar between treatment groups. The most frequently occurring AEs (excluding diseases under study) were arthralgia (PBO 16.93 vs UST 16.56), headache (16.43 vs 16.50), nausea (13.25 vs 11.94), and abdominal pain (14.59 vs 11.54); infections were nasopharyngitis (16.26 vs 18.11) and upper respiratory tract infection (11.40 vs 11.36). For serious infections, the CD-specific event of anal abscess occurred in PBO 2.02 and UST 0.90 pts per 100 PY. When CD-specific events were excluded, overall rates of serious infections were similar between UC and CD. The only malignancy (excluding NMSC) reported in >1 UST-treated patient was prostate cancer; no lymphomas were reported through 1 year. Two pts receiving UST (0.12 per 100 PY; both had UC) died from events that investigators considered to be unrelated to study agent (esophageal varices hemorrhage and acute respiratory failure during thyroid surgery). CONCLUSION: The safety profile of UST in pts with UC and across integrated IBD indications through 1 year was favorable and consistent with the established safety profile in pts with CD and psoriatic disease. (Figure Presented).

Estudio primario

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DOSE ADJUSTMENT IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS: RESULTS FROM THE UNIFI MAINTENANCE STUDY LONG-TERM EXTENSION

Revista Gastroenterology
Año 2020
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Background: The UNIFI randomized-withdrawal maintenance study evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients (pts) with moderately to severely active ulcerative colitis (UC) who had responded to intravenous (IV) UST during induction. We evaluated the efficacy of UST dose adjustment during the long-term extension (LTE). Methods: At Week (Wk) 0 of the 44wk maintenance study, 523 pts who had responded to IV UST induction were randomly assigned in a 1:1:1 ratio to placebo (PBO) SC, UST SC 90 mg q12w, or UST SC 90 mg q8w. Pts who completed the maintenance study were eligible to enter the LTE if the investigator thought they would benefit from continued treatment. PBO pts were discontinued from the LTE after the maintenance study was unblinded and the analysis was complete. Based on the investigator’s clinical judgement of their UC disease activity, pts in the LTE were eligible to receive dose adjustment starting at Wk 56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). PBO pts were only eligible for dose adjustment before unblinding. Pts were assessed for symptomatic remission, partial Mayo scores, and inflammatory markers ≥16 wks after dose adjustment. Results: Symptomatic remission was maintained through Wk 92 among pts treated with UST regardless of dose adjustment in the LTE (Figure). Overall, 40 (28.4%) and 37 (25.9%) pts in the q12w and q8w groups, respectively, underwent dose adjustment (or sham dose adjustment) prior to Wk 92 of the LTE. Among pts who received dose adjustment at Wk 76 or before and had data ≥16 wks after dose adjustment, symptomatic remission was observed in 70.0% in the q12w-to-q8w group and 71.4% in the q8w-to-q8w group, the majority of whom were in symptomatic remission at the time of the dose adjustment (Table). The safety profile of UST in pts who received dose adjustment was generally consistent with the overall safety profile of UST. Conclusion: Pts may benefit from UST dose adjustment to q8w. However, the majority of UST-treated pts were in symptomatic remission at the time of dose adjustment in this study. No new safety signals were observed among pts who dose adjusted.

Estudio primario

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Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy

Revista Alimentary pharmacology & therapeutics
Año 2020
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Background: The ongoing UNIFI long‐term extension evaluates subcutaneous ustekinumab for moderate‐to‐severe ulcerative colitis (UC) from weeks 44 through 220. Aims: To assess efficacy (through week 92) and safety (through week 96) during the long‐term extension. Methods: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long‐term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12 weeks and at each dosing visit after unblinding. Safety was evaluated throughout. Results: Among all patients randomised in maintenance, symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long‐term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid‐free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient‐years (PY) of follow‐up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non‐melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. Conclusions: The efficacy of ustekinumab in patients with UC was sustained through 92 weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236).

Revisión sistemática

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Efficacy of ustekinumab versus advanced therapies for the treatment of moderately to severely active ulcerative colitis: a systematic review and network meta-analysis.

Revista Current medical research and opinion
Año 2020
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Objective : To compare the relative efficacy of ustekinumab (UST) versus other therapies for 1-year response and remission rates in patients with moderate-severe UC. Methods : Randomised controlled trials reporting induction and maintenance efficacy of anti-TNFs (infliximab [IFX], adalimumab [ADA], golimumab [GOL]), vedolizumab (VDZ), tofacitinib (TOF) or UST were identified through a systematic literature review. Analyses were conducted for clinical response, clinical remission and endoscopic-mucosal healing for populations with and without failure of prior biologics (non-biologic failure, NBF; biologic failure, BF). Maintenance data from trials with re-randomised response designs were re-calculated to correspond to treat-through arms. Bayesian network meta-analyses (NMA) were conducted to obtain posterior distribution probabilities for UST to perform better than comparators. Results : Six trials included NBF patients and four included BF patients. In NBF patients, UST as a 1-year regimen showed higher probabilities of clinical response, remission and endoscopic-mucosal healing versus all treatments: Bayesian probabilities of UST being better than active therapies ranged from 91% (VDZ) to 100% (ADA) for response; 82% (VDZ) to 99% (ADA) for remission and 82% (IFX) to 100% (ADA and GOL) for endoscopic-mucosal healing. In BF patients, UST was the most effective treatment (Q8W dose); however, effect sizes were smaller than in the NBF population. Conclusions : Results indicate a higher likelihood of response, remission and endoscopic-mucosal healing at 1 year with UST versus comparators in the NBF population. In BF patients, a higher likelihood of response to UST versus most comparators was also observed, although results were more uncertain.

Estudio primario

No clasificado

Healthcare Cost Offsets from Reductions in Ulcerative Colitis-Related Hospitalizations and Surgeries in Patients Treated with Ustekinumab in the UNIFI Study

Revista American Journal of Gastroenterology
Año 2020
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INTRODUCTION: Ulcerative colitis (UC) affects a growing number of patients (pts) in the US. Avoiding costly hospitalizations and surgeries is critical for all stakeholders including pts and payers. Ustekinumab (UST) was recently approved for treatment of moderately-to-severely active UC in the US, but evidence of its impact on healthcare cost reductions in UC-related hospitalizations and surgeries is lacking. Objective: To model costs from UC-related hospitalizations and surgeries in pts treated with either placebo (PBO) or UST (induction followed by UST 90 mg q8w) in the UNIFI Phase 3 trial over a period of 52 weeks (1 year). METHODS: Eligible UC pts were first enrolled in a randomized induction trial. Clinical responders to intravenous UST were then randomized 1:1:1 in the 44-week randomized-withdrawal maintenance trial to PBO, UST 90 mg q12w, or UST 90 mg q8w. Only the pts on PBO, 6 mg/kg (induction) or UST 90 mg q8w (FDA approved dosing regimen, UST hereafter) in the UNIFI study were analyzed. Number of pts with a UC-related hospitalization and surgery was recorded in both the induction and the maintenance trials of the UNIFI study. Mean costs for UC-related hospitalizations and surgeries were obtained from the literature (adjusted to 2019 US dollars). Per-pt-per-year (PPPY) costs were calculated RESULTS: 322 UST and 319 PBO pts were analyzed in the induction trial of UNIFI, where UST pts had fewer UC-related hospitalizations (1.6% vs 4.4% for PBO) and UC-related surgeries (0% vs 0.6% for PBO) resulting in per-pt cost offsets of ≥638 and $372, respectively, for UST vs PBO during induction. 176 UST and 175 PBO pts were analyzed in the maintenance trial, where UST pts had fewer UC-related hospitalizations (1.7% vs 5.7% for PBO) and UC-related surgeries (0.6% vs 1.7% for PBO) resulting in per-pt cost offsets of ≥911 and $682, respectively, for UST vs PBO during maintenance. Overall, UST pts had per-pt-per year cost offsets of $2,603 from reductions in UC-related hospitalizations and surgeries compared to PBO. CONCLUSION: Moderately-to-severely active UC pts treated with UST had cost offsets vs PBO from fewer UC-related hospitalizations and surgeries in UNIFI study over 1 year. Results are likely conservative as only single events per pt were recorded, and PBO pts in maintenance were re-randomized following response to active induction with UST, meaning non-responders to active drug did not enter the maintenance trial.

Estudio primario

No clasificado

Efficacy of ustekinumab for ulcerative colitis in patients through 3 years: Unifi long-term extension

Revista The American Journal of Gastroenterology
Año 2021
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Introduction: Ustekinumab (UST), an IL-12/23p40 antagonist, is approved for the treatment of moderate-to-severe ulcerative colitis (UC). The UNIFI long-term extension (LTE) evaluates the ongoing efficacy of UST 90 mg SC maintenance therapy. We report the efficacy data through 3 years of treatment including the subgroups based on biologic treatment history. Methods: During the maintenance phase of UNIFI, 523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). Patients (pts) who completed 44 (wks) of maintenance were eligible for the LTE. 284 UST pts entered the LTE, with pts on PBO discontinued after wk44 unblinding. Pts remained in their treatment allocation initially. Beginning at wk56, randomized pts with worsening UC could adjust to q8w dosing (including sham adjustment if already receiving q8w dosing). Efficacy endpoints included symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0), biomarkers (CRP and fecal calprotectin), as well as disease-specific quality of life assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). Results: During the maintenance study, 348 pts were randomized to UST, including 174 bio naïve pts, 161 biologic failure pts, and 13 pts who were biologic-experienced but did not have documentation of biologic failure. Among all pts randomized to UST (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 185 pts (55.2%) were in symptomatic remission at wk152 and 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Among biologic naïve pts, 115 (66.1%) were in symptomatic remission at wk152 and 97.4% (112/115) of pts in symptomatic remission at wk152 were corticosteroid-free. Among biologic failure pts, 70 (43.5%) were in symptomatic remission at wk152 and 94.3% (66/70) of pts in symptomatic remission at wk152 were corticosteroid-free. Median CRP at wk152 in randomized pts treated with UST in the LTE was 1.5 mg/L. Median fecal calprotectin at wk152 was 151.0 mg/kg. Of the randomized pts treated with UST in the LTE and in IBDQ remission at maintenance baseline, 74.6% were in IBDQ remission at wk140. Conclusion: Symptomatic remission, control of inflammation as measured by CRP and fecal calprotectin levels, and improved quality of life as measured by the IBDQ were observed among pts treated with UST through 3 years.

Estudio primario

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Corrigendum: Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy (Aliment Pharmacol Ther., (2020), 52, 11-12, (1658-1675), 10.1111/apt.16119)

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Revista Alimentary Pharmacology and Therapeutics
Año 2021
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In the article entitled “Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy” by Panaccione et al,1 the authors have identified the following three errors as listed below. Although these errors do not change the overall study conclusions, they may impact the interpretation of some of the results presented in the paper. In Table 2, the maintenance baseline values shown for Mayo score are actually the long-term extension baseline values which already appear in Supplemental Table S1. The correct maintenance baseline values are shown below. Also, in Table 2 the second column header should read “Ustekinumab 90 mg q12w” as shown below. (Table presented.) Figure 6 incorrectly summarised the numbers of patients with adverse events (or specific adverse event category) per 100 years of exposure instead of the numbers of adverse events (or specific adverse event category) per 100 years of exposure for the second year results. The corrected figure showing the numbers of events per 100 years of exposure for the second year and footnotes is shown below. 6 FIGURE (Figure presented.) All adverse events (A) and key safety events (B) during ustekinumab exposure†,‡,§,¶,††. †Includes (1) data from Week 44 through Week 96, or up to the dose adjustment if patients had a dose adjustment during the long-term extension, for patients who were in clinical response to ustekinumab IV induction dosing and were randomised to placebo SC on entry into the maintenance study; and (2) data from Week 44 through Week 96 for patients who were in clinical response to placebo IV induction dosing and received placebo SC on entry into the maintenance study. ‡Includes data from Week 44 through Week 96, or up to the dose adjustment if patients had a dose adjustment during the long-term extension for patients who were in clinical response to ustekinumab IV induction dosing and were randomised to ustekinumab 90 mg SC q12w on entry into the maintenance study. §Includes: (1) Patients who were in clinical response to ustekinumab IV induction dosing and were randomised to receive ustekinumab 90 mg SC q8w on entry into the maintenance study, with data from Week 44 through Week 96; (2) Patients who were in clinical response to ustekinumab IV induction dosing, randomised to receive placebo SC or ustekinumab 90 mg SC q12w on entry into the maintenance study, and had a dose adjustment to ustekinumab 90 mg SC q8w, with data from the time of dose adjustment onward; (3) Patients who were not in clinical response to ustekinumab at induction Week 8 but were in clinical response at induction Week 16 after a SC administration of ustekinumab at induction Week 8 and received ustekinumab 90 mg SC q8w on entry into the maintenance study, with data from Week 44 through Week 96. ¶Confidence intervals based on an exact method assuming that the observed number of events follows a Poisson distribution. ††Infection as assessed by the investigator In Supplemental Figure S5, the number of ustekinumab-treated patients with calprotectin data summarised over time should be as shown in the following corrected figure: (Figure presented.) Supplemental Figure S5. Change from maintenance baseline in fecal calprotectin concentrations from Week 44 through Week 92; patients randomized to ustekinumab maintenance therapy and treated in the long-term extension†, ‡, § The authors apologise for these errors.

Estudio primario

No clasificado

Safety of Ustekinumab in Inflammatory Bowel Disease: pooled Safety Analysis of Results from Phase 2/3 Studies

Revista Inflammatory bowel diseases
Año 2021
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BACKGROUND: Ustekinumab is currently approved globally in Crohn's disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn's disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses. METHODS: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or ~6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received ≥1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient‐years of follow‐up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time‐to‐event analyses for serious adverse events and serious infections were also performed. RESULTS: Through 1 year, 2574 patients received ustekinumab (1733 patient‐years of follow‐up). The number of patients with adverse events per 100 patient‐years (placebo 165.99 [95% CI, 155.81‐176.67] vs ustekinumab 118.32 [95% CI, 113.25‐123.55]), serious AEs (27.50 [95% CI, 23.45‐32.04] vs 21.23 [95% CI, 19.12‐23.51]), infections (80.31 [95% CI, 73.28‐87.84] vs 64.32 [95% CI, 60.60‐68.21]), serious infections (5.53 [95% CI, 3.81‐7.77] vs 5.02 [95% CI, 4.02‐6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00‐0.93] vs 0.40 [95% CI, 0.16‐0.83]) were similar between placebo and ustekinumab. CONCLUSIONS: The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications. CLINICALTRIALS.GOV NUMBERS: NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236.

Estudio primario

No clasificado

Efficacy and Safety of Maintenance Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension.

Revista Journal of Crohn's & colitis
Año 2022
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BACKGROUND AND AIMS: The UNIFI long-term extension (LTE) study reports the efficacy and safety of subcutaneous 90 mg ustekinumab through three years of maintenance therapy. METHODS: Patients randomized to ustekinumab q12w or q8w at maintenance baseline (N=348) and randomized ustekinumab-treated patients in the LTE (N=284) were evaluated. Symptomatic remission (Mayo stool frequency=0/1, rectal bleeding=0) was assessed. Safety included all LTE patients (N=188 placebo and N=457 ustekinumab). RESULTS: Among patients randomized to the ustekinumab q12w and q8w groups at maintenance baseline, 54.1% and 56.3% achieved symptomatic remission at week 152. Overall, 20% of patients discontinued ustekinumab, 10% of biologicnaïve and 30% of biologic-exposed patients. Among patients in symptomatic remission at year 3, 94.6% and 98.0% of patients were also corticosteroid free. Corticosteroid-free symptomatic remission rates in the ustekinumab q12w and q8w groups were 51.2% and 55.1% at week 152. Remission rates were higher for biologic-naïve patients than those with a history of biologic failure. Biochemical evidence of response was demonstrated by stable, decreased CRP and fecal calprotectin measurements over 3 years.From weeks 96-156, no deaths, major adverse cardiovascular events, or tuberculosis occurred. Nasopharyngitis, ulcerative colitis and upper respiratory tract infection were most frequently reported. One ustekinumab-treated patient with a history of basal cell carcinoma (BCC) reported 2 BCC. One patient in the q8w ustekinumab group who was receiving concomitant 6-mercaptopurine experienced SAEs of neutropenic sepsis and oral herpes. CONCLUSION: Efficacy of ustekinumab in patients with ulcerative colitis was confirmed through 3 years. No new safety signals were observed.