bluuebunny/crossref_metadata_2025_split huggingface dataset:
P663 Efficacy of tofacitinib in patients with ulcerative colitis after previous ineffective biological therapies
Authors: Rutka M , Farkas K , Pigniczki D , Szántó K , Anita B , Bor R , Fábián A , Szepes Z , Nagy F , Molnár T 
Published: January 2020

Abstract

Background
Tofacitinib (TFC) is an oral, small-molecule Janus kinase inhibitor, which was recently approved for moderate to severe ulcerative colitis (UC). The aim of the current real-life study was to determine efficacy of TFC induction therapy regarding the clinical response and remission in patients with active UC. We evaluated short-term efficacy data in a Hungarian cohort with prior exposure to other biological agents such as anti-TNF drugs and vedolizumab.

Methods
In this single-centre retrospective study, patients with TFC introduction were included. Since January 2019, a total of 16 patients received an oral TFC induction therapy in a dose of 10 mg twice daily for 8 weeks. Endoscopic activity was evaluated by endoscopic Mayo (eMayo) score before the introduction of TFC and in case of an inadequate therapeutic response to the 5-mg-therapy to confirm therapeutic decision-making. Based on the evaluation of clinical symptoms and laboratory parameters, we either kept the dosage or reduced the dose to 5 mg according to local regulations. We also collected data from the 16. and 24. weeks of the therapy. Primary endpoints were a clinical response (as a reduction in partial Mayo Score [pMayo] by minimum 3 points) or remission (as a Mayo score of the maximum of 2 points and without blood in stool) at week 8.

Results
Sixteen patients had received the induction therapy (mean age: 36 years, 7 males and 9 females) in our centre. After 8 weeks, 12 (75%) patients responded to the TFC induction therapy and 6 (37.5%) of them were in remission. Four patients were primary non-responders (25%). Corticosteroid therapy (18 ± 7 mg) was required during the induction in 4 responder cases, which could be stepped down by week 8. As a continuous maintenance therapy, 4 patients have already reached the 16th week and 8 have completed the 24th week. By the end of the follow-up, 12 patients responded and 10 was in remission. During the observation period, 3 patients had to remain on 10 mg TFC dose, 6 patients required dose escalation from 5 mg to 10 mg and 5 mg was sufficient in case of only 3 patients after the introduction. Endoscopic activity showed a moderate decrease from 2.5 ± 0.5 eMayo score to 2 ± 1 (n = 7) until week 16. In respect the responder patients, CRP levels decreased from the mean of 7.23 to 5.02. No serious side-effects were observed during the follow-up.

Conclusion
After the 8-week TFC induction therapy, the response rate was high and only every fourth patients were non-responder. A low number of patients had adequate reactions to the 5 mg-therapy after the introduction, but TFC is effective with dose-escalation in respect of clinical response and remission in patients with UC, who have had an inadequate response to previous biological therapy.
P674 Monitoring posologic change in adalimumab intensification dosing regimen from 40 mg every week to 80 mg every other week
Authors: Diz Lois Palomares M T , Porta Sánchez Á , Elberdin Pazos L , González Conde B , Outeda Macías M , Vázquez Rey M T , Guerrero Montañés A , Estévez Prieto E 
Published: January 2020

Abstract

Background
The previous usual adalimumab (ADA) intensification regimen was 40 mg every week (ew)). Recently the original laboratory commercialised the 80 mg injection pen, with pharmacokinetic studies indicating an alternative intensification dose of 80 mg every other week (eow) similar to 40 mg ew, even though interchangeability has not been assessed in clinical practice. In the biosimilars era, this pen was sold to many Hospitals at the same price as the 40mg pen. For this fact and for patient comfort, we proposed our stable-intensificated-ADA IDB patients on a 40 mg ew regimen, to change the dose to 80 mg eow (clinical practice).

Methods
In this setting, we designed an observational study to monitor clinical, analytical and pharmacokinetic outcomes through this posologic change, for patients who signed the Informed Consent. Clinical (Harvey–Bradshaw index (HBI), partial Mayo score), analytic parameters and ADA trough levels were prospectively obtained at baseline, 4 and 8 months after posologic change. We describe the evolution of this cohort and calculate savings.

Results
12 from 18 patients initially evaluated for new dose regimen were finally changed. All of them agreed to participate in the study. Eighty-three per cent were CD patients, 58% males, median age 51 years old (intecuartil range (IQR) 42–55). Median age at IBD diagnosis was 34 years (IQR 24–44). In 9 patients ADA was the first-line biologic. Median IBD duration before starting ADA was 6 years (IQR 5–8). Median time from ADA initiation to intensification was 31 months (IQR 14–55). The median time of ADA intensification was 37 months (IQR 30–66). Seventy per cent of patients were on immunosuppressors (IS) at the start of the study. Table 1 shows the results of clinical, analytical variables and ADA trough levels at baseline, 4 and 8 months. No differences were found. At 4 months, all patients maintained ADA 80 mg eow. Two patients referred mild worsening, (HBI from 3–4 to 5–6) without significant changes in CRP, calprotectin or ADA levels. They recovered after restoring the previous regimen (ADA 40mg ew). At 8 months, ADA was stopped in one patient in remission with undetectable ADA levels and positive ATI. Total savings in the first 8 months were 59022 €.

Conclusion
in IBD patients with stable response to ADA intensification regimen of 40 mg ew, changing to 80mg eow seems to maintain response and similar trough levels, although some patients may perceive mild symptoms. Economic savings are 50% per patient.
P675 CT-Scout platform, the digital solution to boost patient recruitment in inflammatory bowel disease clinical trials: A multicentre prospective observational comparative study
Authors: Bouhnik Y , Hebuterne X , Raith M , Amiot A , Tanasa Stefanescu C , Laharie D , Roblin X , Bourreille A , Nancey S , Sabbah N , Peyrin Biroulet L 
Published: January 2020

Abstract

Background
The main issue to validating new molecules in the field of IBD is insufficient patient enrollment into clinical trials, resulting in premature trials termination and cost increase. CT-SCOUT™ platform is a web-based solution to help clinicians to pre-screen potential candidates and facilitating the coordination of the research team. Our aim was to compare the number of patients enrolled in IBD clinical trials in sites equipped or not with CT-SCOUT™.

Methods
We conducted a prospective, multicenter, open-label, observational study in sites participating to phase 3 trials evaluating the efficacy and safety of etrolizumab in ulcerative colitis (UC, Hickory) and in Crohn’s disease (CD, Bergamot). Recruitment figures were provided by the sponsor, and we considered the 21 French sites equipped with CTscout and 134 sites in other countries not equipped with CT-SCOUT™. The primary endpoint was the mean number of patients randomised per site in both trials. Secondary endpoints included a mean number of patients randomised in each study. Patients screened and those finally randomised were compared in sites equipped and non-equipped using one-way ANOVA followed by post-hoc Tukey test and Mann–Whitney test.

Results
During the observational period of 40 months (September 2015–December 2018), 644 and 289 patients were screened and randomised in Hickory and/or Gardenia, respectively. There were 307 and 149 patients in 78 sites for Hickory, and 337 and 140 patients for Bergamot in 102 sites. The mean numbers of screened and randomised patients in CT-SCOUT™ equipped sites vs. non-equipped are given in the table.
The mean number of patients randomised in Hickory in CT-SCOUT™ sites increased by 4.0 folds as compared with non-equipped sites (p &lt; 0.001). The mean number of patients randomised in Bergamot in CT-SCOUT™ equipped sites has been increased by 1.9-folds as compared with non-equipped sites (p = 0.009).

Conclusion
This multicentric study demonstrated a significant increase in patient recruitment in IBD clinical trials. Randomisation rates were twice to four times higher in equipped sites compared with non-equipped ones. CT-SCOUT™ appears to be a promising digital solution to the global issue of patient enrollment in clinical trials.
P683 Infliximab, adalimumab and vedolizumab levels are not altered by pregnancy progression in IBD patients and neonatal vedolizumab levels are lower than in mothers: Results from the PICCOLO study
Authors: Flanagan E , GIbson P R , Rosella O , Ross A , Bell S J 
Published: January 2020

Abstract

Background
Optimal timing for the last intrapartum dose of biologic agents is controversial. We established that cord blood levels of anti-TNF agents in exposed infants are greater than maternal levels,1 and another study with limited observations suggested maternal infliximab (IFX) levels increased in pregnancy but adalimumab (ADA) levels did not.2 The effect of pregnancy on vedolizumab (VDZ) levels, and placental transfer and time to clearance of VDZ in exposed infants remain undefined.

Methods
We performed a prospective observational study of maternal anti-TNF and VDZ levels pre-conception, in each trimester of pregnancy, at delivery and post-partum where possible. Women with IBD on IFX, ADA or VDZ who were pregnant or planning pregnancy were recruited. Serum trough IFX and ADA levels were measured by ELISA (Q-INFLIXI and Q-ADA (Matriks Biotek, Turkey) or Promonitor (Grifols, Spain)) and VDZ levels by ELISA (Theradiag, France). Infant VDZ levels were measured from the umbilical cord at delivery and at around 6–8 weeks and 3 months to assess time to clearance.

Results
Forty-nine patients (24 IFX, 14 ADA, 11 VDZ) with at least two observations on stable dosing were included. The median number of levels per patient was 3 (range 2–5). Infliximab cohort (n = 24): Median IFX levels were stable (Figure 1). IFX was administered 6–8 weekly at doses of 5 mg/kg (n = 21) or 10 mg/kg (n = 2) except for one patient on 4-weekly dosing. The last dose was given at a median 32 weeks; 3 remain pregnant. Adalimumab cohort (n = 14): Median ADA levels were stable (Figure 1). Twelve were on ADA fortnightly and 2 on weekly. Eleven continued ADA throughout pregnancy and 3 stopped at 30–33 weeks; 2 remain pregnant. Three patients were induced in pregnancy at least 12 weeks before the earliest ADA level. Vedolizumab cohort (n = 11): Trough VDZ levels were stable (Figure 2). Eight patients were on 8-weekly dosing and three were on 4-weekly. The last dose was given at a median 30 weeks; 4 remain pregnant (Patients H-K). Vedolizumab in infants (n = 8): The median VDZ cord blood level was 4.95 (1–19) μg/ml with a median infant:maternal ratio of 0.6 (0.4–0.9). VDZ was cleared at 8 weeks of age in three infants and by 15 weeks in two infants.

Conclusion
The stability of maternal levels of IFX, ADA and VDZ during pregnancy indicate that intrapartum dosing adjustment and routine therapeutic drug monitoring for patients in remission are not needed. Unlike anti-TNF, infant VDZ levels were lower in cord blood than in mothers and were cleared by 15 weeks.

References
P684 The effect of tofacitinib on serum lipids and cardiovascular safety in patients with ulcerative colitis: updated results from the tofacitinib ulcerative colitis clinical programme
Authors: Sands B E , Taub P R , Feagan B G , Armuzzi A , Damião A O , Lawendy N , Solano G , Kwok K , Woolcott J , Salese L , Su C 
Published: January 2020

Abstract

Background
Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical programme, the majority of patients did not have cardiovascular (CV) risk factors at baseline (BL), and increases in lipid levels occurred primarily during induction and remained elevated to Week 61 during maintenance; lipid ratios were relatively unchanged.1 Here, we present updated results of lipid levels in the ongoing, open-label, long-term extension (OLE) study (NCT01470612) and major adverse CV events (MACE) in the Phase 3/OLE tofacitinib UC clinical programme.

Methods
Lipid levels were assessed at multiple time points, and changes from OLE study BL to Month 48 in the OLE study were evaluated. Lipid-lowering agent (LLA) use (proportion of patients) and adjudicated MACE (proportion of patients and incidence rate [IR; unique patients with events per 100 patient-years] with 95% confidence interval [CI]) were reported in patients with UC in two Phase 3, 8-week, placebo-controlled induction studies (OCTAVE Induction 1 and 2; NCT01465763, NCT01458951), a Phase 3, 52-week, placebo-controlled maintenance study (OCTAVE Sustain; NCT01458574) and the OLE study (data as of May 2019; database not locked).

Results
No major changes in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, LDL-c:HDL-c and TC:HDL-c from OLE study BL were observed at Month 48 of the OLE study (Table). In the Phase 3/OLE programme (n = 1124), 7.7% of patients had a new LLA added and 1.9% of patients had their LLA dose increased. Seven MACE were reported (IR 0.26; 95% CI 0.11, 0.54; 2654.66 patient-years); the IR has remained stable since Dec 2016 (IR 0.24; 95% CI 0.07, 0.62).1 Reported MACE was one each of myocardial infarction, acute myocardial infarction, acute coronary syndrome, cerebrovascular accident, haemorrhagic stroke, cerebellar haemorrhage and aortic dissection. Both myocardial infarction events and the acute coronary syndrome event led to temporary tofacitinib discontinuation; the haemorrhagic stroke, cerebrovascular accident and cerebellar haemorrhage led to permanent tofacitinib discontinuation; and the aortic dissection resulted in death. Of the seven patients with MACE, five had CV risk factors at BL.

Conclusion
At Month 48 of the OLE study, lipid levels and ratios remained generally unchanged from OLE study BL following tofacitinib treatment. MACE were infrequent, with the IR remaining stable since the previous report.1 Limitations include low patient numbers and short tofacitinib exposure duration. Longer-term observation studies will further assess risk.

Reference
P686 Expression of CD39 ectonucleotidase on regulatory T cells and on T helper 17 cells in children with IBD receiving anti-TNF therapy
Authors: Petrichuk S V , Radygina Т , Illarionov A , Kuptsova D , Potapov A , Fisenko A P 
Published: January 2020

Abstract

Background
CD39, CD73 ectonucleotidases convert extracellular ATP (eATF) to adenosine. eATF is known to have pro-inflammatory activity, and adenosine has anti-inflammatory activity. It was shown decreasement CD39 expression on regulatory T lymphocytes (Treg) during exacerbation in adult patients with IBD. The aim of this study was to evaluate the expression of CD39 on Treg and Th17 lymphocytes (Th17) in children with inflammatory bowel diseases (IBD) with different responses to anti-TNF therapy.

Methods
The study included 68 children with IBD (CD 35 patients, UC 33 patients) aged 4–18 years with duration of the disease from 6 months till 15 years. All patients were treated with anti-TNF (infliximab, adalimumab) during 11–86 weeks. Clinical response was evaluated according to PUCAI (UC) and PCDAI (CD) scores. Group 1 (n = 35) included patients with exacerbation during anti-TNF therapy, in Group 2 (n = 25) patients with sustained remission. The expression of CD39 on Treg (CD3CD4CD25CD127low) and Th17 cells (CD3CD4CD161) was determined by flow cytometry (NovoCyte Acea Biosciences, Inc.). Statistical analysis was performed using nonparametric Mann–Whitney test and ROC analysis (SPSS Statistics 20).

Results
It were observed inflammatory activity increasement according to PUCAI (Med 40 [30–65], p = 0.8 × 10–5) and PCDIA scores (Med 28.8 [15–55], p = 1.2 × 10–5) in Group 1 in comparison with Group 2. The amount of Treg expressing CD39 (Treg CD39) was 6–58% from Treg (6–80 cl/μl), and the amount of Th17 with the CD39 marker (Th17CD39) was 0.5–57% (2–49 cl/μl). A direct correlation was revealed between TregCD39 and Th17CD39 (r=0.55 p = 1 × 10–6). It was shown that the number of TregCD39 and Th17CD39 does not depend on the age of the child. However, with an increase in the duration of the disease, a decrease in the absolute amount of Th17CD39 is observed (r = −0.3, p = 0.016). In patients Group 1 there was a significant reduction of CD39 expression on Treg (p = 0.00002) and on Th17 (p = 0.0009) compared with a Group 2 in both diseases. The dependence of TregCD39 on PUCAI (r = −0.5 p = 0.013) and PCDAI (r = −0.43 p = 0.03) was revealed. ROC analysis showed that the cut-off level for groups 1 and 2 is 31.7% for TregCD39 (AUC=0.77; Se 69%, Sp 68%) and 37 cl/μl (AUC=0.907; Se 88%, Sp 88%). Cut-off level for the absolute amount of Th17CD39 was 21 cl/μl (AUC=0.888; Se 79%, Sp 81%).

Conclusion
The decreasement in the amount of TregCD39 below 31 cl/μl and Th17CD39 below 21 cl/μl is associated with an exacerbation of the disease. The expression level of ectonucleotidase CD39 on Treg and Th17 in children with IBD receiving anti-TNF therapy is independent of age and allows to differentiate the state of remission and exacerbation.
P687 Early and sustained improvement in stool frequency and rectal bleeding following 52 weeks of mirikizumab treatment
Authors: D’Haens G R , Hibi T , Ferrante M , Bhandari B R , Berliba E , Tuttle J L , Lissoos T , Krueger K , Morris N , Arora V , Naegeli A N , Feagan B G 
Published: January 2020

Abstract

Background
Interleukin (IL)-23 is a key cytokine in inflammatory bowel disease pathogenesis. Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in patients with moderate-to-severely active ulcerative colitis (UC) during 52 weeks of a Phase 2 randomised clinical trial (AMAC, NCT02589665). The effects of miri on stool frequency (SF) and rectal bleeding (RB) through Week 52 are reported.

Methods
Patients (Mayo score 6–12 with endoscopic subscore [ES] ≥2) were randomised 1:1:1:1 to receive intravenous (IV) placebo (n = 63), miri 50 mg (n = 63) or 200 mg (n = 62) with possibility of exposure-based (EB) dose increases, or fixed miri 600 mg (n = 61) every 4 weeks (Q4W). Responders to miri at Week 12 (9-point Mayo score decrease ≥2 points and ≥35% change from baseline, with RB=0 or 1 or decrease ≥1) were re-randomised 1:1 into a double-blind maintenance period to receive miri 200 mg subcutaneously (SC) Q4W (n = 47) or every 12 weeks (Q12W; n = 46), and were treated through Week 52. Patients reported UC symptoms, including SF and RB, via a daily diary. Changes from baseline in average Mayo SF and RB subscores at Weeks 2, 4, and 12 were analysed using a mixed model repeated-measures method to account for missingness and baseline characteristics.

Results
Significant improvement in SF was observed as early as Week 2 in the miri 600 mg Q4W group and as early as Week 4 in the miri 200 mg Q4W group (Figure). Similarly, significant improvement in RB was observed as early as Week 2 in both the miri 200 mg Q4W and 600 mg Q4W groups. Patients who received miri 200 mg Q4W or 600 mg Q4W had a significantly greater reduction in both SF and RB compared with placebo at Week 12 (all p &lt; 0.001) (Figure). Patients who achieved clinical response at Week 12 and were treated with miri 200 mg SC Q4W or SC Q12W maintained a low average SF and RB score at Week 52.

Conclusion
Significant improvements in SF and RB occurred as early as Week 2 of induction treatment and continued to improve during maintenance treatment with mirikizumab. These data demonstrate the early efficacy and longer-term effects of an IL-23p19 antibody on these patient-reported outcomes.
P689 Patient-reported outcomes (PRO-2) and intestinal ultrasound in ulcerative colitis patients: subanalysis of the TRUST&UC study cohort
Authors: Maaser C , Helwig U , Fischer I , Rath S , Kolterer S , Kucharzik T 
Published: January 2020

Abstract

Background
Patient-reported Outcomes (PRO) are gaining increasing acceptance as new tools to evaluate clinical activity, especially in the context of clinical trials and evaluation of drug efficacy. However, data to support the relevance of these endpoints and their correlation to objective markers of inflammation is still lacking.1 Recently published data demonstrated the feasibility of intestinal ultrasound (IUS) as a routine monitoring technique in clinical practice for Crohn’s disease (CD) and ulcerative colitis (UC) patients.2 Thus, the importance and significance of IUS, as a patient-centric and non-invasive technique has emerged over the last years and will become more relevant in the future.With this sub-analysis of the TRUST&UC study, we aimed to investigate the correlation between improvement in ultrasound parameters and PRO-2 in UC patients.

Methods
TRUST&UC is a prospective, observational study including 244 patients with an increased bowel wall thickness (BWT) at baseline and active UC (SCCAI ≥ 5). These patients were analysed for the Simple Clinical Colitis Activity Index (SCCAI) subscores stool frequency, urgency and rectal bleeding. These parameters were documented for up to 4 visits (baseline, an optional visit at week 2, week 6 and week 12). Pathological stool frequency was defined as a stool frequency of ≥1 point (≥ 4 stools/day) and pathological rectal bleeding was defined as ≥1 point (traces of blood in stool); the combination of both subscores was defined as PRO-2.

Results
We found a positive moderate correlation between BWT and the investigated SCCAI-subscores (rectal bleeding and BWT at W12 r = 0.417; stool frequency and BWT at W12, r = 0.483; PRO-2 and BWT at W12, r = 0.518) and even W6, which is in accordance with previously reported correlations of various PROs and endoscopy in UC-patients.3 We demonstrate that patients with normalisation of BWT (sigmoid colon &lt; 4.0 mm) had a significantly higher chance of a non-pathological PRO-2 (pathological PRO-2 yes/no: 4.25 mm and 3.20 mm for week 6 (p &lt; 0.001) and 4.45 mm and 3.00 mm (p &lt; 0.001) for week 12).

Conclusion
With this sub-analysis of the TRUST&UC study we demonstrated that bowel wall thickness, assessed by intestinal ultrasound, had a moderate correlation with normalisation of patient-reported outcomes as early as week 6 and 12. Furthermore, patients with non-pathological PRO-2 had significantly decreased bowel wall thickness. This again supports the value of intestinal ultrasound in routine medical practice.

References