Recommendations for Standardizing Clinical Trial Design and Endoscopic Assessment in Postoperative Crohn’s Disease

2021 ◽  
Author(s):  
Jurij Hanzel ◽  
Vipul Jairath ◽  
Peter De Cruz ◽  
Leonardo Guizzetti ◽  
Lisa M Shackelton ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Trial Design ◽  
Clinical Trial Design ◽  
End Point ◽  
Endoscopic Remission ◽  
Medical Therapies ◽  
Endoscopic Assessment

Abstract Background The lack of standardized methods for clinical trial design and disease activity assessment has contributed to an absence of approved medical therapies for the prevention of postoperative Crohn’s disease (CD). We developed recommendations for regulatory trial design for this indication and for endoscopic assessment of postoperative CD activity. Methods An international panel of 19 gastroenterologists was assembled. Modified Research and Development/University of California Los Angeles methodology was used to rate the appropriateness of 196 statements using a 9-point Likert scale in 2 rounds of voting. Results were reviewed and discussed between rounds. Results Inclusion of patients with a history of completely resected ileocolonic CD in regulatory clinical trials for the prevention of postoperative recurrence was appropriate. Given the absence of approved medical therapies, a placebo-controlled design with a primary end point of endoscopic remission at 52 weeks was appropriate for drug development for this indication; however, there was uncertainty regarding the appropriateness of a coprimary end point of symptomatic and endoscopic remission and the use of currently available patient-reported outcome measures. The modified Rutgeerts Score, endoscopic assessment of the anastomosis, and a minimum of 5cm of neoterminal ileum were also appropriate; although the appropriateness of other indices including the Simple Endoscopic Score for CD for endoscopic assessment of postoperative CD activity was uncertain. Conclusions A framework for regulatory trial design for the prevention of postoperative CD recurrence and endoscopic assessment of disease activity has been developed. Research to empirically validate end points for these trials is needed.

scholarly journals Relevance of monitoring transmural disease activity in patients with Crohn’s disease: current status and future perspectives

2021 ◽  
Vol 14 ◽  
pp. 175628482110066
Author(s):  
Rune Wilkens ◽  
Kerri L. Novak ◽  
Christian Maaser ◽  
Remo Panaccione ◽  
Torsten Kucharzik
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Symptom Control ◽  
Current Status ◽  
Clinical Relapse ◽  
Cross Sectional ◽  
Treatment Targets ◽  
Endoscopic Remission ◽  
Transmural Inflammation

Treatment targets of inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD) have evolved over the last decade. Goals of therapy consisting of symptom control and steroid sparing have shifted to control of disease activity with endoscopic remission being an important endpoint. Unfortunately, this requires ileocolonoscopy, an invasive procedure. Biomarkers [C-reactive protein (CRP) and fecal calprotectin (FCP)] have emerged as surrogates for endoscopic remission and disease activity, but also have limitations. Despite this evolution, we must not lose sight that CD involves transmural inflammation, not fully appreciated with ileocolonoscopy. Therefore, transmural assessment of disease activity by cross-sectional imaging, in particular with magnetic resonance enterography (MRE) and intestinal ultrasonography (IUS), is vital to fully understand disease control. Bowel-wall thickness (BWT) is the cornerstone in assessment of transmural inflammation and BWT normalization, with or without bloodflow normalization, the key element demonstrating resolution of transmural inflammation, namely transmural healing (TH) or transmural remission (TR). In small studies, achievement of TR has been associated with improved long-term clinical outcomes, including reduced hospitalization, surgery, escalation of treatment, and a decrease in clinical relapse over endoscopic remission alone. This review will focus on the existing literature investigating the concept of TR or residual transmural disease and its relation to other existing treatment targets. Current data suggest that TR may be the next logical step in the evolution of treatment targets.

Multiparametric Evaluation Predicts Different Mid-Term Outcomes in Crohn’s Disease

2018 ◽  
Vol 36 (3) ◽  
pp. 184-193 ◽  
Author(s):  
Lucrezia Laterza ◽  
Anna Chiara Piscaglia ◽  
Laura Maria Minordi ◽  
Iolanda Scoleri ◽  
Luigi Larosa ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Mucosal Healing ◽  
Hospitalization Rate ◽  
Clinical Activity ◽  
Ct Enterography ◽  
Complementary Information ◽  
Endoscopic Remission ◽  
Rutgeerts Score

Aim: To evaluate if a single and/or combined (clinical, endoscopic and radiological) assessment could predict clinical outcomes in Crohn’s disease (CD). Methods: We prospectively evaluated 57 CD cases who underwent both a colonoscopy and a CT-enterography (CTE). Harvey-Bradshaw Index (HBi), SES-CD (and/or Rutgeerts score) and the radiological disease activity were defined to stratify patients according to clinical, endoscopic and radiological disease activity respectively. Hospitalizations, surgery, therapeutic changes and deaths were evaluated up to 36 months (time 1) for 53 patients. Results: CTE and endoscopy agreed in stratifying disease activity in 47% of cases (k = –0.05; p = 0.694), CTE and HBi in 35% (k = 0.09; p = 0.08), endoscopy and HBi in 39% (k = 0.13; p = 0.03). Taken together, CTE, endoscopy and HBi agreed only in 18% of cases (k = 0.01; p = 0.41). Among the 11 cases with mucosal healing, only 3 (27%) showed transmural healing. Patients with endoscopic activity needed significantly more changes of therapy compared to patients with endoscopic remission (p = 0.02). Patients with higher transmural or clinical activity at baseline required significantly more hospitalizations (p < 0.01). Hospitalization rate decreases with an increase in the number of parameters indicating remissions at baseline (p = 0.04). Conclusions: Clinical, endoscopic and radiological assessments offer complementary information and could predict different mid-term outcomes in CD.

scholarly journals Distinct patterns of disease activity over time in patients with active SLE revealed using latent class trajectory models

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
John A. Reynolds ◽  
Jennifer Prattley ◽  
Nophar Geifman ◽  
Mark Lunt ◽  
Caroline Gordon ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Trial Design ◽  
Drug Exposure ◽  
Latent Class ◽  
Clinical Trial Design ◽  
Steroid Dose ◽  
Trajectory Models ◽  
Over Time

Abstract Background Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune condition for which there are limited licensed therapies. Clinical trial design is challenging in SLE due at least in part to imperfect outcome measures. Improved understanding of how disease activity changes over time could inform future trial design. The aim of this study was to determine whether distinct trajectories of disease activity over time occur in patients with active SLE within a clinical trial setting and to identify factors associated with these trajectories. Methods Latent class trajectory models were fitted to a clinical trial dataset of a monoclonal antibody targeting CD22 (Epratuzumab) in patients with active SLE using the numerical BILAG-2004 score (nBILAG). The baseline characteristics of patients in each class and changes in prednisolone over time were identified. Exploratory PK-PD modelling was used to examine cumulative drug exposure in relation to latent class membership. Results Five trajectories of disease activity were identified, with 3 principal classes: non-responders (NR), slow responders (SR) and rapid-responders (RR). In both the SR and RR groups, significant changes in disease activity were evident within the first 90 days of the trial. The SR and RR patients had significantly higher baseline disease activity, exposure to epratuzumab and activity in specific BILAG domains, whilst NR had lower steroid use at baseline and less change in steroid dose early in the trial. Conclusions Longitudinal nBILAG scores reveal different trajectories of disease activity and may offer advantages over fixed endpoints. Corticosteroid use however remains an important confounder in lupus trials and can influence early response. Changes in disease activity and steroid dose early in the trial were associated with the overall disease activity trajectory, supporting the feasibility of performing adaptive trial designs in SLE.

scholarly journals P516 Serological biomarkers of tissue remodeling are associated with endoscopic remission in Crohn’s disease patients treated with GED-0301 (mongersen)

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S494-S495
Author(s):  
J Mortensen ◽  
B Feagan ◽  
A C Bay-Jensen ◽  
M A Karsdal ◽  
G Horan ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Tissue Remodeling ◽  
Serum Levels ◽  
Induction Phase ◽  
Collagen Formation ◽  
Endoscopic Remission ◽  
Endoscopic Score ◽  
Serological Biomarkers

Abstract Background In Crohn’s disease (CD) Smad7 is overexpressed in the intestinal mucosa, where it contributes to a sustained production of inflammatory cytokines, increased matrix metalloproteinase (MMP) activity and chronic inflammation through inhibition of the anti-inflammatory actions of TGF-beta. GED-0301, an anti-sense oligodeoxynucleaotide complementary to the mRNA of Smad7, inhibits the translation and synthesis of the Smad7 protein. We investigated exploratory biomarkers of collagen degradation by MMPs (C1M, C3M, C4M) and collagen formation (PRO-C3, PRO-C4 and PRO-C5) and their association with endoscopic remission in CD patients treated with GED-0301. Methods 63 CD patients were randomized (1:1:1) to 4, 8 or 12 weeks oral, blinded GED-0301 160 mg daily (ClinicalTrials.gov no: NCT02367183). Simple endoscopic score for CD (SES-CD) (centrally read) was used to evaluate disease activity. Remission was defined as a SES-CD≤4 score at week 12. 54 CD patients completed the 12-week induction phase. Serum biomarkers measured by competitive ELISA se included C1M, C3M, C4M, PRO-C3, PRO-C4, PRO-C5 at baseline, week 4, week 8 and week 12. Spearman rho correlation was applied to evaluate the association with biomarkers and SES-CD score. Results Seven patients (11%) achieved a SES-CD≤4 at week 12. At baseline and at week 12 the biomarkers, C1M (baseline: r=0.36, P=0.005; wk12: r=0.47, P=0.0007), C3M (baseline: r=0.46, P=0.0002; wk12: r=0.28, P=0.047), C4M (baseline: r=0.40, P=0.002; wk12: r=0.36, P=0.011) PRO-C4 (baseline: r=0.36, P=0.004; wk12: r=0.35, P=0.013), and PRO-C5 (baseline: r=0.30, P=0.022) correlated with SES-CD (table 1). Remitters at baseline showed a numerically lower serum levels of C1M (54ng/mL vs. 65ng/mL), C3M (14.7ng/mL vs. 16.5ng/mL), PRO-C4 (241ng/mL vs. 299ng/mL) and PRO-C5 (442ng/mL vs. 660ng/mL) compared to non-remitters. The biomarkers C1M (P&lt;0.05), C4M (P&lt;0.05) and PRO-C5 (P&lt;0.05) were significantly suppressed in remitters at week 12 compared to non-remitters (figure 1). The same biomarkers also demonstrated sustained suppression of serum concentrations at week 4, 8 and 12 (C1M: 21.6% decrease from baseline at week 12; C4M: 15% decrease from baseline at week 12; PRO-C5: 26.6% decrease from baseline at week 12) in remitters compared to non-remitters. Conclusion Biomarkers of tissue remodeling correlated with the SES-CD scores of CD patients treated with mongersen. Patients s who achieved remission based on endoscopic criteria showing greater suppression of these biomarkers relative to non-remitters. Collectively, these data suggest that biomarkers of tissue remodeling may be useful to monitoring disease activity and mucosal changes in CD patients.

Issues in clinical trial design II: Selection of end point measures

Neurology ◽  
1996 ◽  
Vol 47 (Issue 4, Supplement 2) ◽  
pp. 100S-102S ◽  
Author(s):  
M. B. Bromberg ◽  
B. R. Brooks
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design ◽  
End Point ◽  
Selection Of

scholarly journals P180 Endoscopic scoring systems for Crohn’s Disease and Ulcerative Colitis and their correlation with histological and clinical outcomes

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S251-S252
Author(s):  
E Gibbons ◽  
T Hayes ◽  
C K Shahzad ◽  
A Hussain ◽  
B Hall ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Response To Treatment ◽  
Median Score ◽  
Histological Assessment ◽  
Mayo Score ◽  
Wide Range ◽  
Endoscopic Remission ◽  
Histological Remission

Abstract Background Endoscopy and histopathology are vital for evaluating disease activity and treatment response in inflammatory bowel disease. Correlation between endoscopic and histological indices has not been fully examined. The primary aim of this study was to examine the correlation of endoscopic scores with histological assessment and association with flare/hospitalisation in the ensuing 12 months. Methods We selected 100 random colonoscopies performed for IBD surveillance/assessment in 2019. Adult patients with a complete colonoscopy were included. All reports were blindly scored by 2 expert endoscopists using SES CD or Mayo score as appropriate. Histology was retrieved from HistoLab database and classified as normal, mild, moderate and severe. Clinical demographics, CRP, fecal calprotectin levels, flare episodes and hospitalisations were recorded. Correlation between endoscopic and histologic activity was tested. Comparisons were made between patients in histologic and endoscopic remission v those with endoscopic and histologic activity regarding association with flare/hospitalisation. Results 100 IBD patients (median age 49 IQR 22; 54% female; 50% Crohn’s disease) were included. A wide range of SES-CD scores were noted (median score 2 and IQR 6). 48% were in remission (0–2), 34% mild with score 3–6, 18% moderate with score 7–15 and 4% severe disease activity scoring &gt; 16. Of those in endoscopic remission, 87.5% had normal histology. Of the 9 with moderate endoscopic disease all ranges of histological status were described. All levels of the Mayo scale (median score 1) were represented. Similar to the Crohn’s group, 87.5% of those in endoscopic remission also had normal histology. In total 42 patients were in both endoscopic and histological remission, and only 7% experienced a flare of disease activity in the following 12 months, with no hospitalisations. In total 40 patients had both endoscopically and histologically active disease, and 45% of these had a flare in the ensuing 12 months with two hospitalisations.The ROC curve for SES-CD score and histological remission is 0.73 +/- 0.07 95%CI 0.59 -0.87 and for the Mayo score and histological remission 0.87 +/- 0.05 95%CI 0.78- 0.97. Conclusion Accurate assessment of disease activity guides therapy choices and helps assess response to treatment in our IBD cohort. In this study the SES-CD and Mayo endoscopic scores showed good correlation with histological assessment. Those with active endoscopic and histologic disease experienced more flares and had higher rates of hospitalisation than those in remission. Further investigation with higher study numbers and incorporation of a standardised histological grading system are required.

P112 STUDY OF THE PROTEOMIC PROFILE IN PATIENTS WITH CROHN’S DISEASE, ITS CORRELATION WITH DIAGNOSIS AND DISEASE ACTIVITY

2018 ◽  
Vol 154 (1) ◽  
pp. S58
Author(s):  
Salah Badr El-Din ◽  
Ezzat Ahmed ◽  
Doaa Header ◽  
Pacint Moez ◽  
Mohamed Ibrahim
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Proteomic Profile

Localization and Activity of Inflammatory Bowel Disease Using 111ln Leukocyte Imaging

1988 ◽  
Vol 27 (03) ◽  
pp. 83-86 ◽  
Author(s):  
B. Briele ◽  
F. Wolf ◽  
H. J. Biersack ◽  
F. F. Knapp ◽  
A. Hotze
Keyword(s):  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Bowel Disease ◽  
Cell Uptake ◽  
Disease Extent ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Leukocyte Imaging

A prospective study was initiated to compare the clinically proven results concerning localization/extent and activity of inflammatory bowel diseases with those of 111ln-oxine leukocyte imaging. All patients studied were completely examined with barium enema x-ray, clinical and laboratory investigations, and endoscopy with histopathology. A total of 31 leukocyte scans were performed in 15 patients (12 with Crohn’s disease, 3 with ulcerative colitis). The scans were graded by comparing the cell uptake of a lesion (when present) and a bone marrow area providing a count ratio (CR). The inflammatory lesions were correctly localized on 26 leukocyte scans, and in 21 scans the scintigraphically estimated extent of disease was identical to endoscopy. In 5 cases the disease extent was underestimated, 4 scans in patients with relapse of Crohn’s disease were falsely negative, and in one patient with remission truly negative. The scintigraphically assessed disease activity was also in a good agreement with clinical disease activity based on histopathology in all cases. We conclude that leukocyte imaging provides valuable information about localization and activity of inflammatory bowel disease.

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