scholarly journals OP40 Analysis of clinical features associated with favourable outcomes from ustekinumab treat-to-target strategy in Crohn’s Disease patients in the STARDUST trial

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S039-S039
Author(s):  
S Danese ◽  
S Vermeire ◽  
A Dignass ◽  
J Panés ◽  
G D’Haens ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Activity Index ◽  
Safety Data ◽  
Standard Of Care ◽  
Treat To Target ◽  
Faecal Calprotectin ◽  
Reactive Protein ◽  
Moderate Disease ◽  
Endoscopic Score

Abstract Background The 48-week (W) interventional STARDUST trial assessed whether a treat-to-target (T2T) strategy using ustekinumab (UST) may optimize Crohn’s disease (CD) outcomes; primary efficacy and safety data have been reported before.1 Here we assessed which patient (pt) subgroups may benefit from T2T vs standard of care (SoC) in achieving endoscopic response after 1 year of UST treatment. Methods Adult pts with moderate–severely active CD (CD activity index [CDAI] 220–450) and Simple Endoscopic Score in CD [SES-CD] ≥3) who failed conventional therapy and/or 1 biologic were included. Pts received iv, weight-based UST ~6 mg/kg at W0 (baseline [BL]); then SC UST 90 mg at W8. At W16, CDAI 70 responders were randomized (1:1) to T2T or SoC arms. Pts in the T2T arm were assigned to SC UST q12w or q8w based on 25% improvement in SES-CD score vs BL. From W16–48, UST dose was further intensified up to q4w if the following were not met: CDAI <220 and ≥70-point improvement from BL, and C-reactive protein ≤10 mg/L or faecal calprotectin (FCal) ≤250 µg/g. Pts who failed treatment target despite UST q4w were discontinued. In the SoC arm, UST dose was assigned based on EU SmPC (q12w or q8w). We report the treatment effect for the primary endpoint (endoscopic response [≥50% improvement in SES-CD score vs BL] at W48), evaluated for subgroups of pts, based on demographics at BL. For each subgroup, the odds ratio (OR) and 95% confidence interval (CI) of T2T vs SoC were provided based on the logistic regression model that included treatment arm and stratification factors (prior exposure to biologics [none or 1] and SES-CD score [≤16, > 16] at BL) as independent variables. Results Of 500 pts enrolled, 441 were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3% completed W48. At W48, pts randomized to T2T were more likely to achieve endoscopic response compared to SoC (p<0.05), if they had at BL: (i) longer disease duration (>median [79.1 months]; OR 2.2; 95%CI 1.17–3.94); (ii) clinically moderate disease (CDAI ≤300; OR 1.7; 95%CI 1.03–2.76); (iii) normal FCal (≤250; OR 3.0; 95%CI 1.22–7.56), (iv) endoscopically active CD (SES-CD ≥4 for ileal or ≥6 for colonic and/or ileocolonic disease; OR 1.8; 95%CI 1.10–2.91); and (v) history or presence of strictures/fistula or occurrence of an intra-abdominal abscess (OR 2.3; 95%CI 1.06–5.01 and OR 3.5; 95%CI 1.07–11.19, respectively; Figure 1). Conclusion T2T was more effective than SoC (p<0.05) in achieving endoscopic response after 1 year of UST treatment in certain subgroups including pts with higher endoscopic scores at BL and those with history/presence of bowel damage. Reference

scholarly journals DOP13 Clinical and endoscopic response to ustekinumab in Crohn’s disease: Week 16 interim analysis of the STARDUST trial

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S049-S052 ◽  
Author(s):  
S Danese ◽  
S Vermeire ◽  
G D’Haens ◽  
J Panés ◽  
A Dignass ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Clinical Remission ◽  
Disease Duration ◽  
Activity Index ◽  
Standard Of Care ◽  
Treat To Target ◽  
Faecal Calprotectin ◽  
Intention To Treat

Abstract Background Treat-to-target (T2T) strategy may optimise IBD disease management. We describe interim clinical and endoscopic results of the STARDUST trial in Crohn’s disease (CD) patients, following 16 weeks (W) of ustekinumab (UST) induction. Methods STARDUST, an ongoing phase 3b randomised strategy trial, enrolled adults with moderate–severely active CD (CD activity index [CDAI] 220–450) and simple endoscopic index for CD [SES-CD] ≥3) who failed conventional therapy ±1 biologic. At W0, patients received intravenous, weight-based UST of ~6mg/kg (approved label) and at W8, subcutaneous UST 90mg. At W16, patients with CDAI reduction ≥70 points were randomised (1:1) to T2T or standard of care. Key endpoints (intention-to-treat [ITT] set, as observed) were analysed at W8 and W16: % patients in clinical remission (CDAI score <150); % patients with a clinical response (CDAI <150 or decrease vs. baseline [BL] ≥100 points); faecal calprotectin (FCal) and C-reactive protein (CRP) levels: normalisation of FCal or/and CRP; improvement ≥50% vs. BL (patients with elevated FCal and CRP subpopulations); change vs. BL in CDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) total scores. Patients randomised to T2T underwent colonoscopy at W16 and were analysed for change in SES-CD score vs. BL, endoscopic response (decrease in SES-CD score ≥50% vs. BL) and endoscopic remission (SES-CD score ≤2) (central reading). Results The ITT full set included 500 patients with BL mean (SD) CDAI score 282.3 (65.8), SES-CD 13.1 (8.1), CRP 15.7 (23.4) mg/l, FCal 1741.9 (2932.1) mg/g and disease duration 9.4 (8.7) years; 58.4% previously failed 1 biologic. At W16, 79.4% of patients had a clinical response and 66.6% were in clinical remission. About half of the patients showed ≥50% improvement in FCal and CRP levels, which normalised in about 1/3 of patients. Results were similar irrespective of previous biologic (Table 1); 84% of patients in response at W16 were in clinical remission. Statistically significant changes from BL in CDAI, FCal, and CRP were observed at W8, and in IBDQ scores at W16 (Table 2). In the T2T set (n = 220; CDAI 70 responders), BL characteristics were similar to the full analysis set; SES-CD score was 13.4 (8.8). At W16, 36.8% and 11.4% of patients in the T2T set achieved endoscopic response and remission, respectively. The endoscopic response was independent of BL SES-CD score and disease duration, but numerically better for colonic vs. ileal disease. No new safety signals were reported. Conclusion STARDUST is the first T2T trial in CD patients. After 16 W following induction with UST, 2/3 of patients achieved clinical remission. Thirty-seven per cent of those randomised to the T2T arm (CDAI 70 responders) showed endoscopic response by central reading at W16. Results were similar irrespective of being bio-naïve or failing 1 biologic.

scholarly journals OP35 Effect of maintenance ustekinumab on corticosteroid-free endoscopic and clinical outcomes in patients with Crohn’s Disease - Week 48 analysis of the STARDUST trial

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S032-S033
Author(s):  
S Danese ◽  
S Vermeire ◽  
G D’Haens ◽  
J Panés ◽  
A Dignass ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Primary Endpoint ◽  
Clinical Remission ◽  
Response Rate ◽  
Remission Rate ◽  
Standard Of Care ◽  
Treat To Target ◽  
Clinical Remission Rate ◽  
Endoscopic Score

Abstract Background The STARDUST study demonstrated that ustekinumab (UST), using either a treat-to-target (T2T) or standard of care (SoC) strategy, may induce and maintain endoscopic and clinical response and remission in Crohn’s disease (CD). Primary endpoint, safety, and efficacy have been reported previously.1 Because corticosteroid (CS) sparing is an important aim of CD management, we compared the efficacy of UST T2T vs SoC in achieving CS-free clinical remission and endoscopic response. Methods Adult patients (pts) with moderate–severely active CD who were CDAI 70 responders after 16 weeks (W) of induction, comprising a single dose of UST 6 mg/kg iv followed by UST 90 mg SC at W8, were randomized to either T2T or SoC arms. In the T2T arm, choice of UST maintenance dosage (q12w or q8w) was based on endoscopic improvement at W16, followed by clinical and biomarker-directed dose escalation up to q4w; in the SoC arm, UST q12w or q8w dosage was based on EU SmPC. Primary endpoint was endoscopic response (Simple Endoscopic Score in CD [SES-CD] decrease from baseline [BL] ≥50%) at W48. For pts on CS at W16, CS tapering was mandatory. At W48, CS-free clinical remission (CDAI <150 and no CS for ≥30 days) and CS-free endoscopic response (reduction from BL in SES-CD ≥50% and no CS for ≥30 days) were evaluated. Results Of 500 pts enrolled, 441 achieved a CDAI 70 response at W16 and were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3%, respectively, completed W48. Among clinical remitters and responders at W16 (start of CS tapering), in both T2T and SoC arms more than 70% were still in remission or response at W48 (Figure 1). CS use throughout 48 weeks of treatment is summarized in Table 1. At W48, in T2T and SoC arms similar rates were noted for CS-free endoscopic response (33.6% and 28.5%, respectively) and CS-free clinical remission (56.4% and 63.3%, respectively). Notably, in T2T and SoC arms the CS-free clinical remission rate among pts on CS at BL was 44.1% and 45.1%, respectively (Figure 2). Among W48 endoscopic responders (T2T, n=83; SoC, n=66), CS-free endoscopic response rate was 89.2% and 95.5%, respectively; among W48 clinical remitters (T2T, n=135; SoC, n=154), CS-free clinical remission rate was 91.9% and 90.9%, in T2T and SoC arms, respectively. Conclusion Pts treated with UST under T2T or SoC strategies achieved similar rates of CS-free clinical remission and endoscopic response over 48 weeks. Overall for pts on CS at BL, UST reduced the need for CS while achieving response/remission. Most (>89%) pts with endoscopic response/clinical remission at W48 were also CS-free responders/remitters. Reference

scholarly journals DOP10 Intestinal ultrasound response and transmural healing after ustekinumab induction in Crohn’s disease: Week 16 interim analysis of the STARDUST trial substudy

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S046-S048
Author(s):  
T Kucharzik ◽  
R Wilkens ◽  
G Maconi ◽  
M A D’Agostino ◽  
M Le Bars ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Activity Index ◽  
Randomised Trial ◽  
Standard Of Care ◽  
Early Response ◽  
Response To Treatment ◽  
Treat To Target ◽  
Non Invasive ◽  
Bowel Segments

Abstract Background Intestinal ultrasound (IUS) is a non-invasive tool for evaluating transmural disease activity in Crohn’s disease (CD) patients. We report interim Week (W)16 results from an IUS substudy of STARDUST, a phase 3B randomised trial of CD patients treated with ustekinumab (UST), comparing a treat-to-target (T2T) maintenance treatment strategy vs. standard of care (SoC). The aim of the substudy was to assess changes in IUS parameters, including transmural response to UST induction therapy. Methods Patients (≥18 years) with moderate–severe active CD (CD Activity Index [CDAI] 220–450 and simple endoscopic index for CD [SES-CD] ≥3) who failed conventional therapy and/or 1 biologic, received weight-based IV UST dosing of ~6mg/kg at Week 0, then SC UST 90mg at W8. At Week 16, patients with CDAI reduction ≥70 points were randomised (1:1) to T2T or SoC treatment arms. Exclusion criteria: characteristics precluding IUS visualisation of affected bowel segments and normal bowel wall thickness (BWT) (≤2.0mm terminal ileum; ≤3.0mm colon) for all segments at baseline (BL). Key IUS endpoints assessed at W4, W8 and W16 (central reading): IUS response ≥25% BWT reduction from BL; BWT change from BL (mm); IUS remission (transmural healing) ‒ BWT normalisation, colour Doppler signal ≤1, normal echo stratification, and absence of inflammatory fat. The most affected bowel segment at BL was used for all IUS parameters. Correlations/% agreement between IUS response/remission and clinical (CDAI70, clinical response/remission), biomarker (CRP/FCal levels) and endoscopy outcomes (SES-CD scores) were assessed. Results The analysis included 82/94 patients enrolled in the IUS substudy; n = 76 patients had BL and ≥1 post-BL IUS assessment. BL characteristics were similar to those of the main STARDUST population. Overall IUS response and remission (transmural healing) rates at W16 were 33.8% and 11.3%, respectively (Table 1). The most affected segments were ileum in 66% and colon in 34% of patients, with better outcomes found in the colon (Table 2). BWT and Doppler’s signal started to normalise at W8, inflammatory fat and echo stratification at W16 (Table 2). Mean BWT improvement from BL was statistically significant as early as W4 (p = 0.0002; Table 3). Moderate agreement was observed between earlier IUS responses and later biomarkers/endoscopic improvements. Conclusion This was the first international, interventional, multicentre study using IUS in CD. IUS response to UST was detected as early as Week 4, and a clinically meaningful % of patients achieved transmural healing, primarily in the colon, at W16. IUS could be a valuable tool to detect early response to treatment in CD. Future studies need to confirm whether early IUS response is predictive of long-term outcomes for CD patients.

scholarly journals Heat-shock protein 90α in plasma reflects severity of fatigue in patients with Crohn’s disease

2019 ◽  
Vol 26 (2) ◽  
pp. 146-151 ◽  
Author(s):  
Tore Grimstad ◽  
Ingeborg Kvivik ◽  
Jan Terje Kvaløy ◽  
Lars Aabakken ◽  
Roald Omdal
Keyword(s):  
Crohn’S Disease ◽  
Heat Shock ◽  
Crohn's Disease ◽  
Cross Sectional Study ◽  
Study Data ◽  
Faecal Calprotectin ◽  
Cross Sectional ◽  
Reactive Protein ◽  
Endoscopic Score ◽  
Shock Proteins

Heat-shock proteins (HSPs) are evolutionarily conserved proteins with important cellular homeostasis functions during harmful conditions, including inflammation. Some HSPs are secreted extracellularly and act on distant cells by down-regulating inflammation and increasing cellular stress defence mechanisms. HSP90α has been postulated to signal fatigue in chronic inflammation. We investigated whether HSP90α is associated with fatigue in patients with Crohn’s disease. Fifty-three patients with newly diagnosed Crohn’s disease were included in a cross-sectional study. Data on demographics and disease distribution were obtained. Fatigue was measured by the fatigue visual analogue scale (fVAS). Disease activity was assessed by the Simple Endoscopic Score for Crohn’s disease and Harvey Bradshaw Index. C-reactive protein, faecal calprotectin and HSP90α were also measured. The median fVAS score was 52 mm, indicating significant fatigue. HSP90α scores correlated significantly with fVAS ( r =  0.31, P =  0.03). In a multivariate regression model, HSP90α was the only significant contributor to fVAS scores (β = 0.31, P =  0.03). When patients were dichotomised into groups with high and low HSP90α concentrations, significantly higher fVAS scores were demonstrated in the group with high HSP90α ( M =  62.4, confidence interval 53.0–71.8 vs. 43.3, 31.6–55.0; P =  0.01). Thus, HSP90α may contribute to fatigue generation and/or modulation in patients with Crohn’s disease.

DOP71 Efficacy, safety, and tolerability of ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: Results from, UniStar, a phase 1 study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S107-S108
Author(s):  
J Rosh ◽  
D Turner ◽  
A Griffiths ◽  
D Jacobstein ◽  
O Adedokun ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Opportunistic Infections ◽  
Activity Index ◽  
Phase 1 ◽  
Double Blind ◽  
Faecal Calprotectin ◽  
Adequate Treatment ◽  
Safety And Efficacy ◽  
Paediatric Patients

Abstract Background Ustekinumab (UST) is approved for the treatment of adults with moderate to severe Crohn’s disease (CD). The objective of this study was to evaluate the pharmacokinetics (PK), safety, and efficacy of UST in paediatric patients with moderately to severely active CD who had failed treatment with corticosteroids (CS) and/or immunomodulators (IM) and/or anti-tumour necrosis factor (TNF) therapies. Here, we report the safety and efficacy results through Week 16; PK results are reported separately. Methods This was a Phase 1, multicentre, 16-week, double-blind induction dose-ranging study (NCT02968108) in patients aged 2 to <18 years (body weight [BW] ≥10 kg) with a Paediatric CD Activity Index (PCDAI) score >30 and at least an abnormal C-reactive protein >3.0 mg/l or faecal calprotectin >250 µg/g), or ulcerations in the ileum or colon upon ileocolonoscopy despite adequate treatment with CS ± IM ± anti-TNF therapy. Patients were randomised (1:1) and stratified by weight and prior anti-TNF use for induction to one of 2 weight range-based intravenous (IV) doses: 130mg vs. 390 mg if BW ≥40 kg and 3 mg/kg vs. 9 mg/kg if BW <40 kg. At week 8, all patients received a single subcutaneous (SC) UST maintenance dose of 90mg if BW ≥40 kg or 2 mg/kg if BW <40 kg. Results Forty-four patients (59% ≥40kg BW; >90% anti-TNF exposed) were randomised (n = 23 lower dose; n = 21 higher dose) and treated with UST. Baseline characteristics are summarised in Table 1. At week 16, in the lower dose and higher dose groups, 52%/52% achieved clinical response (reduction in PCDAI ≥15) and 22%/29% had clinical remission (PCDAI ≤10), respectively (Table 2). In addition, 32% and 28% of patients showed endoscopic response (reduction in Simple Endoscopic Score for CD of ≥50%), respectively. Through week 16, 73% of patients reported ≥1 adverse event (AE; 82.6% lower dose vs. 62% higher dose); 2 discontinued due to AEs (1 in each group). Serious AEs occurred in 16% of patients (26% lower dose and 5% higher dose, with CD exacerbation being the most frequent (13%/5%, respectively). Infections occurred in 41% of patients (1 was serious, which was intestinal abscess that spontaneously resolved with sequelae). No injection site reactions, opportunistic infections, malignancies, or deaths were reported. No antibodies to UST were observed. Conclusion As early as 3 weeks and through 16 weeks, both the lower and higher doses of UST (IV week 0 and SC at week 8) improved clinical and endoscopic disease activity in this previously treatment-refractory group of children with CD. The safety profile was consistent with that for UST in adults with CD.

scholarly journals Serum C-reactive protein level does not correlate with Crohn’s Disease Activity Index

2010 ◽  
Vol 5 ◽  
pp. 274-278
Author(s):  
Maciej Kohut ◽  
Katarzyna Kozioł ◽  
Emilia Olek ◽  
Anna Koclęga ◽  
Marek Hartleb
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Protein Level ◽  
Activity Index ◽  
Disease Activity Index ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Crohn’S Disease Activity

scholarly journals P300 Crohn’s Disease Strictures Respond to Drug Treatment and Treat-to-Target Intense Combination Therapy is More Effective than Standard Anti-TNF Therapy. The STRIDENT Randomised Controlled Trial

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S328-S330
Author(s):  
J Schulberg ◽  
E Wright ◽  
B Holt ◽  
T Sutherland ◽  
A Ross ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Drug Therapy ◽  
Crohn's Disease ◽  
Treatment Failure ◽  
Standard Treatment ◽  
Intensive Treatment ◽  
Treat To Target ◽  
Symptom Improvement ◽  
High Dose ◽  
Faecal Calprotectin

Abstract Background Strictures are the commonest complication in Crohn’s disease. Surgery and endoscopic dilation are the main treatments; drug therapy has been considered contra-indicated. Given that most strictures have an inflammatory component we aimed to assess the efficacy of anti-inflammatory therapy, and to identify the optimal treatment. Methods In this randomised trial patients with symptomatic Crohn’s disease strictures and inflammation were assessed by imaging (MRI, colonoscopy, intestinal ultrasound) and for inflammation (faecal calprotectin and CRP). Symptoms were assessed using an Obstructive Symptom Score (OSS). Patients with short endoscopically-accessible strictures had a baseline endoscopic balloon dilation if indicated. Patients were then randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) with 40mg fortnightly maintenance plus thiopurine, with therapy increased for ongoing inflammation at 4 and 8 months, versus standard dose adalimumab mono-therapy. At 12 months primary endpoint was improved OSS. Secondary outcomes: disease activity, treatment failure, stricture morphology, inflammation, psychological well-being, disability, and quality of life. MRI was assessed blindly. Results 52 patients were randomised to the intensive and 25 to the standard treatment arm. 27 of 52 (52%) intensive treatment patients dose escalated at 4 or 8 months. Improved OSS at 12 months occurred in 41 (79%) intensive treatment and 16 (64%) standard treatment arms (P=0.17). Treatment failure was less common in the intensive treatment arm (10%) versus the standard treatment arm (28%) (P=0·045). Faecal calprotectin normalised (<100mcg/g) in 32 (62%) v 11 (44%) (P=0.15), and CRP normalised in 32 (62%) v 11 (44%) (P=0.15), in intensive versus standard treatment arms respectively. MRI stricture morphology improvement (MaRIA score decrease ≥25%) was seen in 31 (61%) v 9 (28%) (P=0.009) and in 40 (78%) v 14 (56%) using the simplified MaRIA score (≥1 point improvement) (P=0.047). Improvement in bowel wall thickness by >25% on ultrasound was seen in 22/43 (51%) and 7/21 (33%) respectively (P=0.18). MRI complete stricture resolution was seen in 10/51 (20%) and 4/25 (16%) (P=0.7). At 12 month colonoscopy 22/48 (46%) v 9/25 (36%) strictures were passable (P=0.42). 12 month median drug levels were 13.2µg/ml and 6.6µg/ml respectively (P<0.0001). See summary results figure 1 and case example figure 2. Conclusion Crohn’s disease strictures are responsive to drug therapy. A majority of patients experience symptom improvement and many have improved stricture morphology. Treat-to-target therapy intensification results in less treatment failure, less stricture-associated inflammation, and greater improvement in stricture morphology.

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