Original Article
Alimentary Tract
Development and Validation of a Clinical Decision Support Tool That Incorporates Pharmacokinetic Data to Predict Endoscopic Healing in Patients Treated With Infliximab

https://doi.org/10.1016/j.cgh.2020.04.078Get rights and content

Background & Aims

Infliximab is an effective treatment for moderate to severe ulcerative colitis (UC). Little is known about patient-related factors that might be used to predict endoscopic healing with infliximab therapy.

Methods

We analyzed data from 484 patients included in the randomized trials of the effects of infliximab therapy for patients with UC (Active Ulcerative Colitis Trials [ACT]-1 and ACT-2). We used a 2-compartment population pharmacokinetic model to calculate baseline infliximab clearance. Two multivariable regression models were derived and validated for their ability to identify patients with endoscopic healing (Mayo endoscopic score, ≤1) at weeks 8 and 30, using only baseline variables. We developed a clinical decision support tool (CDST) and calculator to determine the probability of endoscopic healing in patients starting infliximab.

Results

Higher baseline infliximab clearance, stool frequency, and rectal bleeding scores were associated negatively with endoscopic healing at week 8. In the validation set, a CDST score of 9 points or fewer identified patients without endoscopic healing at week 8 with 82% sensitivity (95% CI, 76%–88%), whereas a CDST score of 16 points or more identified patients with endoscopic healing at week 8 with 87% specificity (95% CI, 81%–94%). Higher baseline infliximab clearance, stool frequency score, white blood cell count, and lower body weight were associated negatively with endoscopic healing at week 30. In the validation set, CDST scores of 17 points or fewer identified patients without endoscopic healing at week 30 with 90% sensitivity (95% CI, 85%–95%), whereas scores greater than 22 points identified patients with endoscopic healing at week 30 with 80% specificity (95% CI, 73%–87%). External validation models had a modest predictive value, with an area under of the curve of 0.67 (95% CI, 0.61–0.74). Patient-level probabilities of endoscopic healing at weeks 8 or 30 can be calculated online (www.premedibd.com).

Conclusions

Using data from 2 clinical trials of patients receiving infliximab therapy for UC, we developed and validated the CDST, which uses data on infliximab clearance and baseline patient and disease measures to identify patients most likely to have endoscopic healing. This tool will facilitate therapy decision making and precision medicine.

Section snippets

Data Assembly

Clinical, endoscopic, and pharmacologic data were available for 484 patients (Active Ulcerative Colitis Trials [ACT]-1, N = 243; ACT-2, N = 241) with moderate-to-severe UC (defined as a total Mayo Clinic score [MCS]14 of 6–12 points and a Mayo endoscopic subscore (MES) ≥2) who participated in 2 double-blind, placebo-controlled, parallel-group, 54- and 30-week studies (Clinicaltrials.gov numbers: NCT00036439 and NCT00096655).3 The ACT-1 (54 weeks) and ACT-2 (30 weeks) trials had similar designs,

Baseline Demographics and Clinical Characteristics

Demographic and clinical characteristics of the patients whose data were part of the derivation (ACT-1) and validation (ACT-2) cohorts were similar at baseline and are shown in Table 1.

Prediction Models

The results of univariable and multivariable logistic regression analysis of baseline factors predictive of endoscopic healing at week 8 and week 30 for patients with UC treated with infliximab are presented in Tables 2 and 3, respectively. Baseline use of concomitant immunomodulators was found to be associated

Discussion

We developed a CDST to calculate the probability of endoscopic healing (defined as MES ≤ 1) in patients with UC based on infliximab clearance and patient- and disease-related factors at baseline, before initiation of infliximab therapy, and validated this tool in a separate independent cohort of patients. The model has modest predictive value for discrimination of patients with high probability of achieving endoscopic healing, a clinically important outcome associated with a lower risk of

Acknowledgments

This study used data obtained from clinical trials sponsored by Janssen. The interpretation and reporting of research using this data are solely the responsibility of the authors and do not necessarily represent the official views of Janssen.

CRediT Authorship Contributions

CRediT Authorship Contributions: Niels Vande Casteele (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Supervision: Lead; Validation: Lead; Writing – original draft: Lead; Writing – review &

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    Conflicts of interest The authors disclose the following: Niels Vande Casteele has received consulting fees from Janssen, Pfizer, Progenity, Prometheus, Takeda, and UCB, and grant/research support from R-Biopharm, Takeda, and UCB; Vipul Jairath has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genentech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Inc, Topivert, and Celltrion, and speaker’s fees from Takeda, Janssen, Shire, Ferring, AbbVie, and Pfizer; Jenny Jeyarajah is an employee of Robarts Clinical Trials, Inc; Parambir Dulai has received consulting fees from Takeda, AbbVie, Janssen, and Pfizer, and research grants from Takeda, AbbVie, Janssen, and Pfizer; Siddharth Singh has received consulting fees from AbbVie, Takeda, Pfizer, and AMAG Pharmaceuticals, and research grants from AbbVie; Lisa M. Shackelton has received consulting fees from Robarts Clinical Trials, Inc; Brian G. Feagan has received consulting fees from Abbott/AbbVie, AdMIRx, Inc, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport, Inc, Aptevo Therapeutics, Asta Pharma, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, Galen/Atlantica, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD, Inc, Intact Therapeutics, JnJ/Janssen, Kyowa Kakko Kirin Co, Ltd, Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestles, Nextbiotix, Novonordisk, ParImmune, Parvus Therapeutics, Inc, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma, Inc, Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared, Ltd, and Zyngenia, speaker’s fees from Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts, and UCB Pharma, grant/research support from AbbVie, Inc, Amgen, Inc, AstraZeneca/MedImmune, Ltd, Atlantic Pharmaceuticals, Ltd, Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech, Inc/Hoffmann-La Roche, Ltd, Gilead Sciences, Inc, GlaxoSmithKline, Janssen Research and Development, LLC, Pfizer, Inc, Receptos, Inc/Celgene International, Sanofi, Santarus, Inc, Takeda Development Center Americas, Inc, Tillotts Pharma AG, and UCB, and is a member of the scientific advisory boards for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics, Inc, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Inc, Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, and UCB Pharma, and is a member of the Board of Directors for Robarts Clinical Trials, Inc; and William J. Sandborn has received consulting fees from AbbVie, Akros Pharma, Allergan, Ambrx, Inc, Amgen, Ardelyx, Arena Pharmaceuticals, Atlantic Pharmaceuticals, Avaxia, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Conatus, Cosmo Technologies, Escalier Biosciences, Ferring, Ferring Research Institute, Forward Pharma, Galapagos, Genentech, Gilead Sciences, Immune Pharmaceuticals, Index Pharmaceuticals, Janssen, Kyowa Hakko Kirin Pharma, Lilly, Medimmune, Mesoblast, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma, Otsuka, Palatin, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Qu Biologics, Regeneron, Ritter Pharmaceuticals, Robarts Clinical Trials, Inc, Salix, Seattle Genetics, Seres Therapeutics, Shire, Sigmoid Biotechnologies, Takeda, Theradiag, Theravance, Tigenix, Tillotts Pharma, UCB Pharma, Vascular Biogenics, and Vivelix, research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, and Celgene/Receptos, payments for lectures/speakers bureau from AbbVie, Janssen, and Takeda, and holds stock/stock options in Escalier Biosciences, Oppilan Pharma, Precision IBD, Progenity, and Ritter Pharmaceuticals.

    Funding Supported by a Research Scholar Award from the American Gastroenterological Association (N.V.C.); American College of Gastroenterology Junior Faculty Development award 144271, a Crohn’s and Colitis Foundation Career Development award 404614, and National Institute of Diabetes and Digestive and Kidney Diseases award K23DK117058 (S.S.); and by a Research Scholar Award from the American Gastroenterological Association (P.S.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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