Association between serum concentration of infliximab and efficacy in adult patients with ulcerative...

Accepted Manuscript

Association Between Serum Concentration of Infliximab and Efficacy in AdultPatients with Ulcerative Colitis

Omoniyi J. Adedokun, MS RPh William J. Sandborn, MD Brian G. Feagan, MDFRCPC Paul Rutgeerts, MD PhD FRCP Zhenhua Xu, PhD, FCP Colleen W.Marano, PhD Jewel Johanns, PhD Honghui Zhou, PhD, FCP Hugh M. Davis, PhDFreddy Cornillie, PhD Walter Reinisch, MD

PII: S0016-5085(14)01074-9DOI: 10.1053/j.gastro.2014.08.035Reference: YGAST 59318

To appear in: GastroenterologyAccepted Date: 26 August 2014

Please cite this article as: Adedokun OJ, Sandborn WJ, Feagan BG, Rutgeerts P, Xu Z, Marano CW,Johanns J, Zhou H, Davis HM, Cornillie F, Reinisch W, Association Between Serum Concentration ofInfliximab and Efficacy in Adult Patients with Ulcerative Colitis, Gastroenterology (2014), doi: 10.1053/j.gastro.2014.08.035.

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http://dx.doi.org/10.1053/j.gastro.2014.08.035

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ACCEPTED MANUSCRIPTGastroenterology resubmission #2

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Short title: Infliximab concentration and clinical outcome in UC

Association Between Serum Concentration of Infliximab and Efficacy in Adult

Patients with Ulcerative Colitis

Omoniyi J Adedokun MS RPh 1, William J Sandborn MD2, Brian G Feagan MD

FRCPC3, Paul Rutgeerts MD PhD FRCP4, Zhenhua Xu PhD, FCP1, Colleen W Marano

PhD1, Jewel Johanns PhD1, Honghui Zhou PhD, FCP1, Hugh M Davis PhD1, Freddy

Cornillie PhD5, Walter Reinisch MD6

1Janssen Research & Development, LLC, Spring House, PA, USA; 2University of

California San Diego, La Jolla, California, USA; 3Robarts Clinical Trials, University of

Western Ontario, London, Ontario, Canada; 4University Hospital Leuven, Herestraat,

Belgium; 5Janssen Biologics BV, The Netherlands; 6Department of Internal Medicine III,

Medical University of Vienna, Vienna, Austria & McMaster University, Hamilton,

Ontario, Canada

Corresponding author and request for reprints: Omoniyi J. Adedokun; Janssen

Research & Development, LLC; 1400 McKean Road, Spring House, PA 19477; tel:

215.793.7220, fax: 215-986-1013, email: [email protected]

Grant support: The ACT-1 and ACT-2 trials were sponsored by Janssen Research &

Development, LLC (formerly Centocor Research & Development).

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Disclosures: All authors must disclose any potential conflicts (financial, professional, or

personal) that are relevant to the manuscript. If the author(s) has nothing to disclose, this

must be stated.

OJ Adedokun is an employee of Janssen Research & Development, LLC.

WJ Sandborn has received consulting fees from Abbott, ActoGeniX NV, AGI

Therapeutics Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM-

Pharma BV, Anaphore, Astellas, Athersys Inc, Atlantic Healthcare Ltd, Aptalis,

BioBalance Corp, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek

Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis,

Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle

Pharmaceuticals, EnGene Inc, Eli Lilly, Enteromedics, Exagen Diagnostics Inc, Ferring

Pharmaceuticals, Flexio Therapeutics Inc, Funxional Therapeutics Ltd, Genzyme Corp,

Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood

Pharmaceuticals, Janssen Pharmaceutical Research & Development, LLC; KaloBios

Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck

Research Laboratories, Merck/Serono, Millenium Pharmaceuticals, Nisshin Kyorin

Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals,

Orexigen Therapeutics Inc, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus

Laboratories, ProtAb Ltd, Purgenesis Technologies Inc, Relypsa Inc, Roche, Salient

Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough, Shire

Pharmaceuticals, Sigmoid Pharma Ltd, Sirtris Pharmaceuticals, SLA Pharma UK Ltd,

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Targacept, Teva Pharmaceuticals, Therakos, Tilliotts Pharma AG, TxCell SA, UCB

Pharma, Viamet Pharmaceuticals, Vascular Biogenics Ltd, Warner Chilcott UK Ltd and

Wyeth; research grants from Abbott, Bristol-Myers Squibb, Genentech,

GlaxoSmithKline, Janssen Pharmaceutical Research & Development, LLC, Millennium

Pharmaceuticals, Novartis, Pfizer, Procter and Gamble, Shire Pharmaceuticals and UCB

Pharma; payments for lectures/speakers bureau from Abbott, Bristol-Myers Squibb and

Janssen Pharmaceutical Research & Development, LLC; and holds stock/stock options in

Enteromedics.

BG Feagan has received research/grant support from Abbott/AbbVie, Amgen, Astra

Zeneca, Bristol-Myers-Squibb, Janssen Biotech (Centocor), Johnson&Johnson/Janssen,

Millennium, Pfizer, Receptos, Roche/Genentech, Santarus, Sanofi, Tillotts, and UCB

Pharma; serves as a consultant to/speaker for Abbott/AbbVie, Actogenix, Albireo

Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Axcan, Baxter Healthcare Corp.,

Boehringer-Ingelheim, Bristol-Myers-Squibb, Calypso Biotech, Celgene, Elan/Biogen,

EnGene, Ferring Pharma, GiCare Pharma, Gilead, Given Imaging Inc., GlaxoSmithKline,

Ironwood Pharma, Janssen Biotech (Centocor), Johnson&Johnson/Janssen, Kyowa

Kakko Kirin Co Ltd., Lexicon, Lilly, Merck/Schering-Plough, Millennium, Nektar,

Novonordisk, Prometheus Therapeutics and Diagnostics, Pfizer, Receptos,

Roche/Genentech, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc.,

Takeda, Teva Pharma, Tillotts Pharma AG, UCB Pharma, Vertex Pharma, Warner-

Chilcott, Wyeth, Zealand, and Zyngenia; and is a Steering Committee member for

Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol-Myers-Squibb,

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Celgene, Elan/Biogen, Ferring, Janssen Biotech (Centocor), Johnson&Johnson/Janssen,

Merck/Schering-Plough, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Salix

Pharma, Takeda, Teva, Tillotts Pharma AG, and UCB Pharma.

P Rutgeerts has received research support from Abbott, Janssen, Merck/Schering Plough,

and UCB; consulting fees from Abbott, Bristol-Meyers-Squibb, Falk Pharma,

Genentech/Hoffman LaRoche, Janssen, Merck/Serono, Merck/Schering-Plough,

Millenium/Takeda, Neovacs, Pfizer, Robarts, Tillots, and UCB; and has served as a

speaker for Abbott, Janssen, and Merck/Schering-Plough.

Z Xu is an employee of Janssen Research & Development, LLC.

CW Marano is an employee of Janssen Research & Development, LLC.

J Johanns is an employee of Janssen Research & Development, LLC.

H Zhou is an employee of Janssen Research & Development, LLC.

HM Davis is an employee of Janssen Research & Development, LLC.

F Cornillie is an employee of Janssen Biologics BV.

W Reinisch has served as a speaker, a consultant and/or an advisory board member for

Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Aptalis, Astellas, Astra

Zeneca, Biogen IDEC, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene,

Centocor, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Galapagos, Genentech,

Grünenthal, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid

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Therapeutics, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, Ocera,

Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical

Trial, Schering-Plough, Setpointmedical, Shire, Takeda, Therakos, Tigenix, UCB, Vifor,

Yakult, Zyngenia, and 4SC.

Writing assistance: Michelle Perate, MS and Mary Whitman, PhD (Janssen Scientific

Affairs, LLC) provided editorial and submission support.

Author contributions: All authors were involved in designing/conducting the clinical

study, contributing data for/interpreting data analyses, drafting/critically reviewing the

manuscript, and approving the final manuscript for submission.

Word count: 5,831/6,000

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Abbreviations:

ACT-1/ACT-2 Active Ulcerative Colitis Trials

ATI antibodies to infliximab

AUC area under curve

CPW2/6/14/30/54 preinfusion concentration at week 2/6/14/30/54

CRP C-reactive protein

CW8 concentration at week 8

EIA enzyme immunoassay

IBD inflammatory bowel disease

LR+ positive likelihood ratio

NPV negative predictive value

PK pharmacokinetic

PPV positive predictive value

ROC receiver operator characteristics

SIC serum infliximab concentration

TNF tumor necrosis factor-α

UC ulcerative colitis

wk week

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ABSTRACT

Background & Aims: We analyzed data collected during the Active Ulcerative Colitis

Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of

infliximab and outcomes of adults with moderate-to-severe ulcerative colitis.

Methods: We compared serum concentrations of infliximab with outcomes of 728

patients with moderately-to-severely active ulcerative colitis who participated in ACT 1

or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only).

Relationships between serum concentration of infliximab and efficacy outcomes were

assessed using trend, logistic regression, and receiver operating characteristic curve

analyses. We also evaluated factors that affect the relationship between exposure and

response.

Results: Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were

significantly higher in patients with clinical response, mucosal healing, and/or clinical

remission than in patients who did not meet these response criteria. There were

statistically significant relationships between quartile of infliximab serum concentration

and efficacy at these time points (P<.01). Infliximab therapy was effective for a smaller

proportion of patients in the lowest quartile, and these patients had lower serum levels of

albumin and a higher incidence of antibodies to infliximab than patients in other

quartiles. Although the relationship between exposure to infliximab and response varied

among patients, approximate serum concentrations of 41 µg/mL infliximab at week 8 of

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induction therapy and 3.7 µg/mL at steady state during maintenance therapy produced

optimal outcomes in patients.

Conclusions: Serum concentrations of infliximab associate with efficacy in patients with

moderately to severe ulcerative colitis. However, complex factors determine the

relationship between exposure to this drug and response. A prospective evaluation of the

value of measuring serum concentrations of infliximab should be performed before these

data can be included in patient management strategies. Clinicaltrials.gov number,

NCT00036439 and NCT00096655

Key words: anti-tumor necrosis factor; monoclonal antibody; pharmacokinetics;

inflammatory bowel disease

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INTRODUCTION

Infliximab is a recombinant chimeric immunoglobulin G-1κ monoclonal antibody that

neutralizes the biologic activity of tumor necrosis factor-α (TNF). Infliximab is approved

for treatment of patients with moderate-to-severe ulcerative colitis (UC) based on the

results of the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) that evaluated 728

patients with moderate-to-severe disease. In these studies, patients treated with infliximab

at weeks 0, 2, 6, and every 8 weeks thereafter were more likely to demonstrate clinical

response, clinical remission, and mucosal healing at weeks 8, 30, and 54 than patients

assigned to placebo.1,2

Previous pharmacokinetic (PK) evaluations of infliximab use in UC have demonstrated a

linear relationship between dose and serum infliximab concentration3 and that the

systemic disposition of infliximab is influenced by body weight, serum albumin, and the

formation of antibodies to infliximab (ATI).4 In addition, serum infliximab

concentrations have been found to influence the response to treatment in Crohn’s

disease,5,6 rheumatoid arthritis,7 and psoriasis.8

Therapeutic drug monitoring can potentially improve outcomes in patients receiving

TNF-antagonists, particularly in those who have lost response to these agents due to

inadequate serum drug concentrations.9 As such, knowledge of the target serum

infliximab concentrations required for efficacy in both induction and maintenance may

improve clinical decision-making in UC.

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Several studies have reported a positive association between infliximab concentration and

efficacy outcomes in patients with inflammatory bowel disease (IBD);10-14 however, there

are limited reports on specific concentration thresholds for optimal efficacy in UC. In one

study that identified specific infliximab cut-off levels, the analysis was based on

concentration data predominantly from patients with Crohn’s disease and included

relatively few patients with UC (n=13).14 Given the differences in pathophysiology and

response to treatment between Crohn’s disease and UC, it is reasonable to expect some

potential differences in the exposure-response relationship of anti-TNF therapies when

used to manage these conditions.9 Hence, evaluation of the relationship between serum

infliximab concentrations and efficacy based on data from well-controlled clinical trials

in UC patients may help identify target serum infliximab concentrations that can be used

to guide therapeutic decisions in an effort to optimize clinical outcomes in these patients.

We performed post-hoc analyses of data from the ACT-1 and ACT-2 trials to assess the

relationship between serum infliximab concentrations and clinical outcomes and to

identify clinically relevant drug concentrations to target in pursuit of better clinical

outcomes.

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PATIENTS AND METHODS

Patients

ACT-1 and ACT-2 (NCT00036439 and NCT00096655) were randomized, double-blind,

placebo-controlled, Phase 3 clinical trials conducted globally. A total of 728 patients

were randomized at 62 sites in ACT-1 (N = 364) and 55 sites in ACT-2 (N = 364). The

institutional review board or ethics committee at each site approved the protocols, and all

patients provided informed consent. A patient disposition flow chart for the present

analyses is shown in Figure 1.

Study design

The ACT-1 and ACT-2 trials were conducted in compliance with the principles of the

Declaration of Helsinki and Good Clinical Practices. The design and conduct of these

trials were reported previously.2 Briefly, all patients had an established diagnosis of

moderately-to-severely active UC, with a Mayo score15 of 6 to 12 points (range: 0 to 12;

higher scores indicate more severe disease activity), despite concurrent treatment with

corticosteroids, azathioprine or 6-mercaptopurine (ACT-1 and ACT-2), or 5-

aminosalicylates (ACT-2 only). Patients diagnosed with indeterminate colitis, Crohn’s

disease, or clinical findings suggestive of Crohn’s disease (i.e., fistula or granuloma on

biopsy) were excluded. As previously described, concurrent therapy was not required at

enrollment for patients who could not tolerate or who previously failed to respond to

these medications.2 Doses of concomitant medications remained constant except for

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corticosteroids, which were tapered to discontinuation following induction and during

maintenance therapy, i.e., from week 8 forward.2

Patients were randomized equally to receive intravenous infusions of infliximab 5 mg/kg,

infliximab 10 mg/kg, or placebo at weeks 0, 2, 6, and then every 8 weeks through week

22 (ACT-2) or week 46 (ACT-1) (Figure S1). Although infliximab is indicated for the

treatment of UC only as a 5 mg/kg dose regimen, for the purpose of these analyses, data

from patients who received the 10-mg/kg dose regimen in the ACT-1 and ACT-2 trials

were included for a more robust evaluation and interpretation of the concentration-

response relationship.

Study evaluations and analyses

Clinical outcomes were assessed using the Mayo score at week 8 (ACT-1 and ACT-2),

week 30 (ACT-1 and ACT-2), and week 54 (ACT-1 only). Clinical response, defined as a

decrease from baseline in the total Mayo score of at least 3 points and at least 30% and

with an accompanying decrease in the rectal bleeding subscore of at least1 point or an

absolute rectal bleeding subscore of 0 or 1, was the primary endpoint for both ACT-1 and

ACT-2. Clinical remission was defined as a total Mayo score of 2 points or lower, with

no individual subscore exceeding 1 point. Mucosal healing was defined by an endoscopy

subscore of 0 or 1.

For PK evaluations, patients were followed through week 54 in ACT-1 or week 42 in

ACT-2. In ACT-1, blood samples for determining serum infliximab concentrations were

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drawn just before and 1 hour after the infusions at weeks 0, 2, 6, 14, and 46, and just

before the infusions at weeks 30 and 38. Additional blood samples for determination of

serum infliximab concentrations were drawn at the week-8 and week-54 non-dosing

visits (Figure S1). In ACT-2, blood samples were drawn just before and 1 hour after the

infusions at weeks 0 and 2, and just before the infusions at weeks 6 and 14. Additional

blood samples for serum infliximab concentration analysis were drawn at the week-8,

week-30, and week-42 non-dosing visits (Figure S1). Serum infliximab concentrations

were determined using a validated enzyme-linked immunosorbent assay,16 with a lower

limit of quantification of 0.1 µg/mL. Of the 484 patients randomized to infliximab (5 or

10 mg/kg) in the ACT-1 and ACT-2 trials, 482 received at least one infusion and had

appropriate serum infliximab concentration data. ATI were determined using an antigen-

bridging enzyme immunoassay (EIA).16 As with other EIAs, this assay was susceptible to

drug interference and was not able to accurately detect ATI in the presence of a

measurable infliximab concentration. For the purpose of this analysis, patients were

classified as positive if ATI were detected in their serum samples at any visit, while all

other patients were regarded as non-positive for ATI.

Statistical analysis

The patient population for these analyses included only those who received at least one

infusion of infliximab 5 or 10 mg/kg. Only patients with available infliximab

concentration data at the time point of interest were analyzed; missing serum infliximab

concentration data were not imputed. Serum infliximab concentrations and efficacy

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outcomes at week 8 (time for induction efficacy endpoints for both ACT-1 and ACT-2),

week 30 (time for maintenance endpoints for both ACT-1 and ACT-2), and week 54

(additional time for maintenance endpoints for only ACT-1) were the primary focus of

these analyses. The prognostic value of earlier infliximab concentrations on subsequent

efficacy outcomes was also evaluated.

Patient characteristics and serum infliximab concentration data were summarized using

descriptive statistics. The correlation between serum infliximab concentrations at

different time points was assessed using the Pearson correlation coefficient. Serum

infliximab concentration data were compared between patients with and without the

specified efficacy outcomes using a 2-sided Wilcoxon-Mann-Whitney two-sample rank-

sum test. Serum infliximab concentrations were also categorized into quartiles, and the

trend of the proportion of patients with clinical outcomes across the quartiles was

evaluated using the 1-sided Cochrane-Armitage trend test. Comparison of the proportions

of patients with a given efficacy outcome across serum infliximab concentration quartiles

or across a given categorical variable was performed using Fisher’s exact test, while the

Kruskal-Wallis test was used to compare continuous variables across quartile groups. The

association between serum infliximab concentration (log-transformed) and clinical

outcomes was further evaluated by multivariable logistic regression modeling.

The effects of covariates (body weight, age, albumin, C-reactive protein [CRP], Mayo

score, sex, ATI status, and the use of immunosuppressive agents and corticosteroids)

were assessed by logistic regression analyses. A backward elimination approach using a

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significance level of .05 for a covariate as a requirement for continued inclusion in the

model was adopted. Receiver-operating-characteristic (ROC) curve analysis was

employed to identify infliximab concentration thresholds associated with efficacy during

induction and maintenance. Optimal thresholds were chosen using the Youden Index,17

which maximizes the sum of the specificity and sensitivity of the ROC curve.

Access to study data

All authors had access to the study data and reviewed and approved the final manuscript.

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RESULTS

Baseline characteristics in patients with PK data

The baseline characteristics of patients who participated in ACT-1 and ACT-2 have been

detailed.2 A summary of characteristics for patients who were randomized to infliximab

treatment in both studies is provided in Table S1.

Serum infliximab concentrations by clinical response status

The distribution of serum infliximab concentrations observed at each visit through week

30 in patients receiving infliximab 5 or 10 mg/kg is depicted in Figure S2. When assessed

by clinical response status (using total Mayo score) at week 8, serum infliximab

concentrations over time were higher among patients with clinical response than among

patients without response, as illustrated for both dose regimens in Figure 2. For each dose

regimen, the median serum infliximab concentration was significantly higher at week 8 in

patients with clinical response or mucosal healing during induction than those not

achieving these endpoints (Table 1). For example, the median serum infliximab

concentration at week 8 in clinical responders was 35.0 µg/mL compared with

25.8 µg/mL in clinical nonresponders for the 5-mg/kg group at week 8. Similar results

were observed for clinical response and mucosal healing during maintenance at week 30

and week 54 (Table 1). For example, in patients who received the 5-mg/kg regimen, the

median trough serum infliximab concentration in clinical responders was several-fold that

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of clinical nonresponders (e.g., 3.9 vs. 1.2 µg/mL at week 30, 5.0 vs. 0.7 µg/mL at week

54).

With respect to clinical remission among patients in the 5-mg/kg group, the median

serum infliximab concentration at week 8 was not significantly higher in week 8 remitters

than in non-remitters (35.1 vs. 30.8 µg/mL; P = .097). By comparison, the difference in

serum infliximab concentrations between remitters and non-remitters at week 8 was

statistically significant for the 10-mg/kg dose group (P = .0002) (Table 1). The median

serum infliximab concentration was significantly higher in remitters than non-remitters at

week 30 (P < .0001) and week 54 (P < .005), regardless of infliximab dose (Table 1).

Although median serum infliximab concentrations were consistently higher in patients

with positive efficacy outcomes than those who failed to achieve these outcomes, there

was some overlap of the distribution of serum infliximab concentrations between these

groups. The overlap was, however, greater during induction at week 8 but less prominent

during maintenance at week 30 or week 54. It also appears that there was more variability

of serum infliximab concentrations in patients who failed to respond during maintenance

(Figure 3).

Efficacy outcomes by serum infliximab concentration quartiles

When assessed by infliximab concentration quartiles, the proportions of patients with

treatment success as defined by multiple outcome measures, i.e., clinical response,

mucosal healing, and/or clinical remission, generally increased with increasing infliximab

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concentration for the 5-mg/kg dose regimen. In each case, a significantly positive

association was observed for the relationship between serum infliximab concentration

quartiles and clinical outcomes (Figure S3). Patients with serum infliximab

concentrations in the lowest quartile consistently were less likely to demonstrate clinical

response, clinical remission, or mucosal healing and had rates of success approaching

those observed in patients assigned to placebo.2 Notably, this finding was still evident

when the quartiles were examined for the 10-mg/kg dose regimen, as illustrated for the

endpoint of clinical response in Figure S4. In general, patients with infliximab

concentrations in the lowest quartile were more likely to have a lower serum albumin

concentration and to be positive for ATI than patients in the other infliximab

concentration quartiles (Table 2).

Logistic regression and identification of optimal infliximab concentration thresholds

for efficacy

Multivariable logistic regression analyses were performed to identify covariates that may

influence the exposure-response relationship for infliximab in UC patients receiving

5 mg/kg or 10 mg/kg during induction and maintenance treatment. The final logistic

regression model for induction treatment through week 8 showed that higher serum

infliximab concentration at week 8, higher body weight, and female gender were

independently associated with clinical response at week 8. Similar analyses conducted

through week 30 of maintenance treatment showed that a higher infliximab concentration

at week 30 and absence of corticosteroid therapy at baseline were independently

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associated with a greater probability of maintaining clinical response at week 30 (Table

S2).

To identify optimal infliximab concentration target thresholds associated with clinical

improvement in UC patients, ROC curves were generated for efficacy endpoints during

both induction and maintenance treatment periods. The ROC curves for the endpoint of

clinical response in patients who received the 5-mg/kg or 10-mg/kg infliximab dose

regimen are shown in Figure 4 for induction and maintenance treatment. Although the

magnitude of the area under the ROC curves (AUC) was moderate for the induction

analysis (0.63 [95% CI: 0.59, 0.68]), i.e. week 8 concentration (CW8) compared with

clinical response at week 8, it was significantly greater than the null value of .5 (P <

.0001). Further, the AUC under the ROC curve for the preinfusion concentration at week

6 (CPW6; 0.62 [95% CI: 0.57, 0.66]) was not significantly different from that using CW8

(P = .553). In contrast, the preinfusion infliximab concentration at week 2 (CPW2) was a

poor predictor of clinical response at week 8 (AUC=0.51).

With respect to the maintenance ROC curve analysis, the AUC was 0.71 (95% CI: 0.66,

0.76) for the week-30 preinfusion concentration (CPW30) versus clinical response at

week 30 ROC curve, and 0.75 (95% CI: 0.68, 0.82) for the week-54 preinfusion

concentration (CPW54) versus clinical response at week 54 ROC curve. The AUC from

the ROC curve of the serum infliximab preinfusion concentration at week 14 (CPW14;

0.68 [95% CI: 0.63, 0.72]) was comparable to that of CPW30 for the clinical response at

week 30 (P = .087), but was not equivalent to that from the CPW54 ROC curve for the

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week-54 clinical response endpoint (P = .041). In addition, the AUC from the CPW30

ROC curve was comparable to that from the CPW54 ROC curve (P = .746).

The ROC analysis identified different target thresholds depending on the time point of

the PK sampling or the efficacy assessment (Table 3). For clinical response at week 8, the

threshold infliximab concentration of 41 µg/mL at week 8 was associated with a

sensitivity, specificity, and positive predictive value (PPV) of 63%, 62%, and 80%,

respectively. Similarly, to maintain clinical response, an infliximab threshold

concentration of 3.7 µg/mL at week 30 was associated with sensitivity, specificity, and

PPV of 65%, 71%, and 82%, respectively. The data at week 54 suggest a range for serum

infliximab concentrations of similar sensitivity, specificity, and PPV, although the data

represent a subset of patients assessed, i.e., only those from ACT-1.

Serum infliximab concentration and subsequent efficacy outcomes

Serum infliximab concentrations at earlier time points were compared between patients

who maintained or who did not maintain an efficacy outcome. Serum concentrations at

week 8 and week 14 were examined for their impact on week 30 outcomes (ACT 1 and

ACT 2 combined), while concentrations at week 30 were examined for their impact on

week 54 outcomes (ACT 1 only). The results of these analyses demonstrate that patients

who previously achieved an efficacy outcome but who subsequently failed to maintain

that outcome exhibited lower serum infliximab concentrations earlier in their therapy

than did patients who maintained the efficacy outcome. This finding is illustrated for the

remission outcome in Figures S5A-C. In general, the lower the infliximab concentration

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at a given time point, the more likely the patients were to fail to maintain remission

(Figures S5D-F). Similar findings were observed when individual infliximab doses were

analyzed, as illustrated in Figures S6A-D.

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DISCUSSION

In these post-hoc analyses of the ACT-1 and ACT-2 data, we have shown a consistent

relationship between serum infliximab concentrations and clinical outcomes including

clinical response, clinical remission, and mucosal healing. These outcomes were

significantly more likely to occur in patients with higher infliximab concentrations than

those with lower drug concentrations. Although these findings are consistent with

previous reports of an association between serum levels of infliximab and efficacy in

patients with IBD, rheumatoid arthritis, and psoriasis,5-8,18-20 this is the largest evaluation

of this relationship that has been performed in patients with UC to date. A positive

exposure-response relationship has also been observed for golimumab (another anti-TNF

biologic) in patients with UC.21

Furthermore, our data originated from large-scale trials that prospectively evaluated a

large number of well-characterized patients. In particular, these analyses included data

for the approved 5-mg/kg dose as well as the highest studied dose in UC (i.e., 10 mg/kg)

and thus covered a wide range of serum infliximab concentrations. As a result, these

analyses provide more precise estimates of threshold concentrations associated with

efficacy and avoid confounding factors present in previous evaluations.

Although the consistency and statistical validity of the observed association indicates that

a positive correlation exists between infliximab concentrations and efficacy, it is

important to contextualize our findings. For induction, the presence of an infliximab

concentration of approximately 41 µg/mL at week 8 was associated with a PPV of 80%

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and a negative predictive value (NPV) of 42% for the outcome of clinical response at

week 8. Based on the specificity and sensitivity values derived from the ROC analysis of

infliximab induction data, patients with serum infliximab concentrations >41 µg/mL have

almost twice the likelihood of achieving clinical response at week 8 compared with those

who do not achieve this target (positive likelihood ratio [LR+] = 1.7). However, for more

effective patient management, it would be preferable to predict the clinical outcome at

week 8 based on earlier measurements.

Accordingly, although our results showed that the preinfusion concentration at week 2

was not predictive of clinical response at week 8, the preinfusion concentration at week 6

may be a predictor of subsequent response. A likely explanation for this finding is that

the serum infliximab concentration at week 6 is more reflective of drug clearance than the

infliximab concentration at week 2, which reflects the initial phase of drug loading.

With respect to maintenance infliximab therapy, the largest amount of data (ACT-1 and

ACT-2 combined) was available at week 30, and the threshold at this time point was

defined by ROC analysis at 3.7 µg/mL, with a PPV of 82% and an NPV of 51% for the

maintenance of clinical response at week 30. These results show that patients with serum

infliximab concentration >3.7 µg/mL at steady state are more than twice as likely to be in

clinical response during maintenance compared with patients who do not achieve this

target (LR+ = 2.3).

Because preinfusion serum infliximab concentration at week 30 is most representative of

steady-state trough concentration for both ACT studies, more weight should be given to

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the threshold estimate from the ROC analyses at this time point compared with the

week-54 maintenance time point in ACT-1. Nonetheless, our analysis showed that

preinfusion serum infliximab concentrations at week 14 may also be predictive of clinical

response during maintenance. Specifically, a serum infliximab concentration ≥ 5.1 µg/mL

at week 14 was also associated with clinical response at week 30. The serum infliximab

concentration threshold of 5.1 µg/mL at week 14 is consistent with that defined by ROC

analysis for week 30 (3.7 µg/mL) when consideration is given to the fact that the

concentration at week 14 is theoretically expected to be slightly higher than the

concentration at week 30 since only 8 weeks (one maintenance dose interval) have

elapsed before the week-14 sampling, following the three induction doses at week 0, 2,

and 6. Furthermore, the threshold serum infliximab concentration of 3.7 µg/mL is

consistent with that estimated for patients with Crohn’s disease in the infliximab

ACCENT 1 trial, in which a serum infliximab level of 3.5 µg/mL at week 14 was

associated with sustained durable response through week 54.22

In these analyses, patients in the lowest infliximab concentration quartile were found to

have a higher incidence of ATI and lower serum albumin concentrations. The effects of

albumin on serum infliximab concentrations and efficacy in UC were reported

previously.23 Although the occurrence of antibodies to TNF-inhibitors has been cited as a

possible cause for loss of therapeutic effect,10,13,24 the multivariable logistic regression

analysis showed that ATI status was not strongly associated with successful induction of

clinical response at week 8 or maintenance of response at week 30. Overall, the data

from the multivariable model suggest that low serum infliximab concentrations (which

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could result from the presence of ATI) are more directly associated with decreased

response rather than just the occurrence of ATI. This finding is consistent with

conclusions from a systematic review of the impact of ATI in Crohn’s disease,25 as well

as previously published findings of the ACT trial, which showed that the clinical

response rate was numerically higher in patients who had inconclusive ATI status (with

higher serum infliximab concentrations) compared with those who tested positive or

negative for ATI (with lower serum infliximab concentrations).2 Furthermore, other

investigators have reported that some ATI may be transient and do not lead to worse

clinical outcomes unless these ATI levels are sustained.26 The persistence of ATI was not

assessed in the current analysis to make this determination.

Notwithstanding this apparent lack of effect of ATI status on efficacy, it should be noted

that since the assay used for these ATI assessments was only able to accurately detect

ATI in the absence of detectable circulating infliximab, and there is likely some bias from

missing data as patients who withdrew early from the study because of lack of efficacy

may not have had a comprehensive assessment of ATIs. It is possible that a higher

proportion of these patients may have developed ATIs than those who continued in the

trial.

Another important finding in the current study is that although patients with the poorest

outcomes generally display relatively lower serum infliximab concentrations, they do so

at both dose levels in the ACT studies. Although the reason for this phenomenon is

unknown, this counterintuitive finding is suggestive of an intricate relationship between

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infliximab pharmacodynamics and its systemic clearance, such that patients who are

more likely to respond better to infliximab have intrinsically lower clearance of the drug.

Since the overall infliximab clearance is unchanged within the dose range evaluated in

the ACT trials,4 this hypothesis could explain why, despite higher infliximab dose and

higher infliximab concentrations, the proportion of patients achieving efficacy outcomes

remained largely unchanged when the respective dose-stratified concentration quartiles

are compared, most strikingly in the lowest infliximab concentration quartiles (Figure

S4). One possible inference from these data is the existence of a group of patients who

may not effectively be treated with infliximab due to high clearance rates, regardless of

the dose. It should be acknowledged, however, that the above hypothesis is not supported

by results of several studies that have shown the benefits of increasing the infliximab

dose in some patients with IBD or rheumatoid arthritis who lose response.27,28

Nonetheless, these findings suggest that clinicians should carefully weigh the need for a

dose adjustment when applicable, considering that not all patients may benefit from such

a dose increase.

The current results have some limitations. First, while the relationship between serum

infliximab concentrations and efficacy outcomes appears to be both consistent and robust,

these results are retrospective and may be confounded by other determinants of both drug

concentrations and outcomes. However, these data were generated from large randomized

trials in which known confounders were prospectively identified and in which

randomization would be expected to balance for the presence of confounding factors

between the experimental groups. Nevertheless, prospective studies designed to assess

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the value of infliximab concentration-guided dose escalation in terms of efficacy and

potential impact on safety could provide valuable information pertaining to a more

optimized approach toward infliximab therapy of UC. One such study suggests that

therapeutic drug monitoring may predict the likelihood of achieving mucosal healing

following infliximab dose escalation in IBD.29 The positive findings of a small

randomized trial of therapeutic drug monitoring in patients with Crohn’s disease who

experienced a loss of response to infliximab are also encouraging.30 It is also generally

held that a therapeutic drug monitoring approach using treatment algorithms in the

management of secondary loss of response may be more rational than empiric dose

escalation.31

The results of these analyses may also be limited by the fact that the serum infliximab

concentrations were measured using a proprietary assay not presently available

commercially. As a result, research is needed to cross-validate the assay with those

available to physicians to help translate these identified infliximab concentrations into

practice settings. In addition, the low NPV and low positive likelihood ratio associated

with the identified threshold imply that false-negative results may be common and

additional clinical judgment will be needed to manage patients who demonstrate

concentrations below the target threshold. Conversely, the magnitude of the PPV at the

identified thresholds may reassure a clinician that a given patient is not under-treated if

serum drug concentrations are above these thresholds.

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In summary, we have established that there is a strong association between serum

infliximab concentration and efficacy outcomes in patients with UC. The predictive value

of serum infliximab concentrations on subsequent efficacy outcomes in these patients

was also demonstrated. These results further highlight the possibility of infliximab dose

optimization, particularly in patients who are likely to fail to maintain efficacy benefit

while receiving the standard dose regimen. The target serum infliximab threshold

concentrations and corresponding time points for infliximab measurement suggested by

the analyses could assist the clinician in understanding the mechanism whereby an

individual patient is not achieving the expected efficacy. Whether these results can be

exploited to achieve better outcomes for patients with UC will need to be assessed in a

prospective study designed to confirm the growing evidence that concentrations of

infliximab may need to be optimized to maintain efficacy, and thus can provide guidance

to clinicians in the management of patients with UC.

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TABLE AND FIGURE LEGENDS

Table 1. Summary of median (interquartile range) serum infliximab concentration

(SIC; µg/mL) by efficacy outcome status in ACT-1 and ACT-2.

Table 2. Summary of patient characteristics by serum infliximab concentration

quartiles (Q) at induction week 8 and maintenance week 30 among patients treated

with infliximab 5 or 10 mg/kg in ACT-1 and ACT-2.

Table 3. Target serum infliximab concentration thresholds for clinical response

based on the receiver- operating-characteristic (ROC) curve analyses among

patients treated with infliximab 5 or 10 mg/kg in ACT-1 and ACT-2

Figure 1. Patient disposition through the pharmacokinetic (PK) analytical time

points of interest in the ACT-1 and ACT-2 trials.

Figure 2. Serum infliximab concentrations over time by clinical response status at

week 8 in patients randomized to infliximab 5 mg/kg (Panel A) or 10 mg/kg (Panel

B) in ACT-1 and ACT-2. The pharmacokinetic profile shown is according to the

sampling times in ACT-1 and ACT-2.

Figure 3. Distribution of infliximab concentrations by efficacy outcome status at

induction week 8 (A), maintenance week 30 (B), and maintenance week 54 (C; ACT-

1 only) among patients treated with infliximab 5 or 10 mg/kg. Box plots below show

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median (solid line in box), interquartile range (upper and lower boundaries of box) and

standard deviation (whiskers).

Figure 4. Receiver-operating-characteristic (ROC) curves for the relationship

between serum infliximab concentrations and clinical response in ACT-1 and ACT-

2 at induction week 8 (A), maintenance week 30 (B), and maintenance week 54 (C;

ACT-1 only) among patients treated with infliximab 5 or 10 mg/kg. CPW2, CPW6,

CW8 (Panel A), CPW14, CPW30 (Panels B and C), or CPW54 (Panel C, ACT-1 only)

represent ROC curves for clinical response and serum infliximab concentrations at weeks

2, 6, 8, 14, 30, or 54, respectively, all preinfusion except week 8 “A=” indicates the area

under the ROC curve.

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[Author names in bold designate shared co-first authors.]

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TABLES

Table 1. Summary of median (interquartile range) serum infliximab concentration (SIC; µg/mL) by efficacy outcome status in ACT-1 and ACT-2.

Week-8 efficacy outcome following infliximab induction treatment Efficacy outcome

Summary statistic

5 mg /kg (n=230)

10 mg/kg (n=216)

Combined 5 & 10 mg/kg (n=446)

Clinical response

Achieved Not achieved Achieved Not achieved Achieved Not achieved N (%) 160 (69.6) 70 (30.4) 153 (70.8) 63 (29.2) 313 (70.2) 133 (29.8) SIC 35.0

(25.0, 50.5) 25.8

(17.8, 39.5) 82.6

(56.7, 108.4) 52.4

(26.1, 91.0) 51.6

(31.7, 85.8) 33.5

(20.8, 64.4) P value1 .0012 < .0001 < .0001

Mucosal healing

N (%) 146 (63.5) 84 (36.5) 142 (65.7) 74 (34.3) 288 (64.6) 158 (35.4) SIC. 36.1

(25.8, 51.6) 26.0

(17.9, 38.8) 83.6

(57.2, 109.8) 52.5

(31.6, 90.5) 53.1

(33.2, 88.8) 33.5

(21.2, 63.1) P value1 < .0001 < .0001 < .0001

Clinical remission

N (%) 87 (37.8) 143 (62.2) 71 (32.9) 145 (67.1) 158 (35.4) 288 (64.6) SIC 35.1

(24.7, 49.0) 30.8

(20.4, 46.5) 89.6

(68.2, 117.3) 68.3

(39.5, 96.6) 49.0

(32.1, 89.6) 42.3

(24.5, 77.6) P value1 .0971 .0002 .0156

Week 30 efficacy outcome during maintenance treatment Efficacy outcome

Summary statistic

5 mg /kg (n=190)

10 mg/kg (n=184)


Clinical response


(0.7, 7.6) 1.2

(0.1, 3.6) 10.9

(3.9, 18.3) 2.2

(0.1, 4.8) 6.2

(2.0, 15.2) 1.2

(0.1, 4.4) P value1 .0006 < .0001 < .0001

Mucosal healing

N (%) 117 (61.6) 73 (38.4) 124 (67.4) 60 (32.6) 241 (64.4) 133 (35.6) SIC 4.1

(1.1, 8.4) 1.0

(0.1, 3.0) 11.5

(3.9, 18.5) 2.3

(0.1, 5.5) 6.5

(2.4, 15.3) 1.2

(0.1, 4.7) P value1 < .0001 < .0001 < .0001

Clinical remission

N (%) 72 (37.9) 118 (62.1) 85 (46.2) 99 (53.8) 157 (42.0) 217 (58.0) SIC 5.0

(2.3, 10.8) 1.2

(0.1, 4.6) 13.3

(6.3, 18.3) 3.7

(0.2, 7.8) 8.0

(3.5, 16.7) 2.0

(0.1, 6.5) P value1 < .0001 < .0001 < .0001

Week-54 efficacy outcome during maintenance treatment (ACT-1 only) Efficacy outcome

Summary statistic

5 mg /kg (n=78)

10 mg/kg (n=80)


Clinical response


(2.5, 9.3) 0.7

(0.1, 2.8) 10.5

(4.8, 19.1) 0.4

(0.1, 5.4) 6.1

(3.0,14.9) 0.7

(0.1,4.2) P value1 .0008 < .0001 < .0001

Mucosal healing

N (%) 54 (69.2) 24 (30.8) 55 (68.8) 25 (31.3) 109 (69.0) 49 (31.0) SIC 5.1

(2.5, 9.8) 1.1

(0.1, 2.7) 10.5

(4.6, 18.9) 0.1

(0.1, 3.1) 6.5

(3.0,14.9) 0.7

(0.1, 3.1) P value1 .0003 .0001 < .0001

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Clinical remission

N (%) 42 (53.9) 36 (46.2) 41 (51.3) 39 (48.8) 83 (52.5) 75 (47.5) SIC 5.0

(2.6, 9.8) 1.9

(0.1, 6.5) 10.9

(5.9, 19.2) 2.2

(0.1, 11.1) 6.8

(3.2, 15.0) 2.1

(0.1,8.1) P value1 .0047 .0004 < .0001

1 P value derived from 2-sided Wilcoxon-Mann-Whitney two-sample rank-sum test comparing patients who achieved versus those who did not achieve the efficacy outcome.

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Table 2. Summary of patient characteristics by serum infliximab concentration quartiles (Q) at induction week 8 and maintenance week 30 among patients treated with infliximab 5 or 10 mg/kg in ACT-1 and ACT-2. Characteristic1 Q1 Q2 Q3 Q4 P value2 Induction week 8, N 111 112 111 112 Continuous variables (median value)

Body weight (kg) 72.3 78.6 74.5 79.1 .035 Age (yr) 42.0 41.0 38.0 39.0 .140 Serum albumin (g/dL) 3.9 4.1 4.1 4.2 < .0001 C-reactive protein (mg/dL) 0.8 0.9 0.8 0.5 .005 Mayo score 9.0 8.0 8.0 8.0 .003

Categorical variables (%) Male 65.8 62.5 55.0 57.1 .338 Positive antibodies-to-infliximab status 14.4 10.7 2.7 1.8 .0002 Concomitant immunomodulator use3 45.1 42.9 47.8 47.3 .881 Corticosteroid use 62.2 57.1 52.3 53.6 .448

Maintenance week 30, N 93 94 93 94 Continuous variables (median)

Body weight (kg) 75.0 76.3 79.0 75.7 .426 Age (yr) 45.0 41.0 40.0 38.0 .104 Serum albumin (g/dL) 4.0 4.1 4.2 4.2 < .0001 C-reactive protein (mg/dL) 0.9 0.8 0.6 0.7 .142 Mayo score 9.0 8.0 8.0 8.0 .13

Categorical variables (%) Male 59.1 59.6 63.4 55.3 .736 Positive antibodies-to-infliximab status 25.8 3.2 3.2 0.0 < .0001 Concomitant immunomodulator use3 29.0 54.3 59.1 44.7 .0002 Corticosteroid use 57.0 54.3 60.2 46.8 .297

1All characteristics are at baseline with the exception of antibodies-to-infliximab status. 2 P value derived from the Fisher’s exact test for categorical variables and the Kruskal-Wallis test for continuous variables. 3Azathioprine, 6-mercaptopurine, or methotrexate

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Table 3. Target serum infliximab concentration thresholds for clinical response based on the receiver- operating-characteristic (ROC) curve analyses among patients treated with infliximab 5 or 10 mg/kg in ACT-1 and ACT-2. Efficacy endpoint Infliximab pharmaco-

kinetic metric ROC analysis metric Estimate

Clinical response during induction at week 8

Concentration at week 8 Threshold (µg/mL) 41.2 Sensitivity 63% Specificity 62% NPV 42% PPV 80%


Clinical response during maintenance at week 30



Clinical response during maintenance at week 54 (ACT-1 only)




NPV = negative predictive value, PPV = positive predictive value

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Patientsrandomizedto infliximab

5 mg/kg(n = 121)


10 mg/kg(n = 122)

Patients withPK sampleincluded inthe analysis

(n = 113)


(n = 108)


(n = 96)


(n = 91)


(n = 78)


(n = 80)

Patientsrandomizedto placebo(n = 121)

Week 8

Week 30

Week 54

Patients randomized in ACT-2(n = 364)


5 mg/kg(n = 121)


10 mg/kg(n = 120)


(n = 117)


(n = 108)


(n = 94)


(n = 93)

Patientsrandomizedto placebo(n = 123)

02

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024

0_v2

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Responder 160 162 160 160 158 149 69 66 66

Nonresponder 79 78 73 70 50 41 14 14 12

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nce

ntr

atio

n (

g/m

L)

Responders Nonresponders

0241_v2

0.1

n =

Responder 157 154 155 153 154 143 65 60 63

Nonresponder 85 85 71 65 48 42 13 14 17

0Week 2 6 8 14 22 30 38* 46* 54*

1

10

100

100010 mg/kg

B

Me

dia

n s

eru

m in

flix

ima

b

co

nce

ntr

atio

n (

g/m

L)

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2_v2

AIn

flix

ima

b c

on

ce

ntr

atio

n a

t

we

ek 8

(µ

g/m

L)

No Yes

Clinical

response

No Yes

Mucosal

healing

Efficacy outcomes at week 8

No Yes

Clinical

remission

10

100

024

4_v2

C

Inflix

ima

b c

on

ce

ntr

atio

n a

t

we

ek 5

4 (

µg

/mL)

No Yes

Clinical

response

No Yes

Mucosal

healing


No Yes

Clinical

remission

0.1

0.0

10.0

1.0

024

3_v2

B

Inflix

ima

b c

on

ce

ntr

atio

n a

t

we

ek 3

0 (

µg

/mL)

No Yes

Clinical

response

No Yes

Mucosal

healing


No Yes

Clinical

remission

0.1

0.0

10.0

1.0

P = < .0001 < .0001 < .0001

n = 125 249 133 241 217 157

P = < .0001 < .0001 .0156

n = 133 313 158 288 288 158

P = < .0001 < .0001 < .0001

n = 53 105 49 109 75 83

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C

0.0

0.2

0.4

0.6

0.8

1.0

Clinical response at week 54

0.0 0.2 0.4 0.6 0.8 1.0

Se

nsitiv

ity

Specificity0

24

6_v3

B

0.0

0.2

0.4

0.6

0.8

1.0


0.0 0.2 0.4 0.6 0.8 1.0

Se

nsitiv

ity

Specificity0

24

5_v3

A

0.0

0.2

0.4

0.6

0.8

1.0


0.0 0.2 0.4 0.6 0.8 1.0

Se

nsitiv

ity

Specificity

CW8, A = .63

CPW6, A = .62

CPW2, A = .51

CPW54, A = .75

CPW30, A = .74

CPW14, A = .67

CPW30, A = .71

CPW14, A = .68

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SUPPLEMENTAL MATERIALS

Supplemental Table S1. Summary of baseline patient characteristics of randomized patients in ACT-1 and ACT-2. Data presented are frequency (%) for categorical data, and median (interquartile range) and mean (standard deviation) for continuous data. ACT-1 ACT-2 Combined studies Characteristic at baseline

5 mg/kg (n=121)

10 mg/kg (n=122)

5 mg/kg (n=121)

10 mg/kg (n=120)

5 & 10 mg/kg (n= 484)

Male, n (%) 78 (64.5) 72 (59.0) 76 (62.8) 68 (56.7) 294 (60.7)

Weight (kg) 79.0 (67.0, 90.4) 80.0 (17.8)

76.1 (64.3, 87.3) 76.9 (17.1)

77.0 (64.3, 88.0) 78.4 (17.8)

75 (67.1, 91.9) 79.6 (20.6)

77.0 (66.0,89.0) 78.7 (18.4)

Age (years) 42.0 (30.0 , 52.0) 42.4 (14.3)

39.0 (29.0, 53.0) 41.8 (14.9)

40.0 (30.0, 50.0) 40.5 (13.1)

39.0 (31.0, 50.0) 40.3 (13.3)

40.0 (30.0, 52.0) 41.3 (13.9)

Albumin (g/dL) 4.1 (3.9, 4.3) 4.1 (0.4)

4.1 (3.8, 4.3) 4.0 (0.4)

4.1 (3.8, 4.4) 4.1 (0.4)

4.1 (3.9, 4.2) 4.1 (0.3)

4.1 (3.8, 4.3) 4.1 (0.4)

C-reactive protein (mg/dL)

0.9 (0.2, 1.7) 1.4 (1.9)

1.0 (0.4, 1.7) 1.6 (2.3)

0.8 (0.2, 1.5) 1.3 (2.3)

0.6 (0.2, 1.3) 1.4 (2.2)

0.8 (0.2, 1.6) 1.4 (2.2)

Disease duration (yrs) 4.1 (2.3, 7.3) 5.9 (5.4)

5.9 (2.8, 11.0) 8.5 (8.1)

5.2 (2.6, 9.2) 6.7 (5.3)

4.8 (2.4, 8.7) 6.5 (5.8)

4.9 (2.5, 9.0) 6.9 (6.3)

Mayo score (0-12) 9.0 (7.0, 10.0) 8.5 (1.7)

8.5 (7.0, 9.0) 8.4 (1.4)

8.0 (7.0, 9.0) 8.3 (1.5)

8.0 (7.0, 9.0) 8.3 (1.6)

8.0 (7.0 , 9.0) 8.4 (1.6)

Positive antibody-to-infliximab status, n (%)

9 (7.4) 5 (4.2) 13 (10.7) 6 (5.0) 33 (6.8)

Immunomodulator use, n (%)

66 (54.5) 59 (48.4) 52 (43.0) 50 (41.7) 227 (46.9)

Corticosteroid use, n (%)

70 (57.9) 73 (59.8) 60 (49.6) 66 (55.0) 269 (55.6)

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Supplemental Table S2. Multivariable logistic regression analysis results for induction and maintenance of clinical response in adult patients with ulcerative colitis treated with infliximab 5 or 10 mg/kg in ACT-1 and ACT-2.

Variable Odds ratio (95% confidence interval)

P value

Induction model (dependent variable: clinical response at week 8) Infliximab concentration at week 8* 1.24 (1.05, 1.46) .011 Body weight 1.02 (1.00, 1.03) .015 Sex (female vs. male) 2.55 (1.56, 4.20) .0002 Maintenance model (dependent variable: clinical response at week 30) Infliximab concentration at week 30* 1.38 (1.23,1.54) < .0001 Corticosteroid use at baseline 0.46 (0.29, 0.75) .0015 *Log-transformed concentration

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Figure S1. Infliximab dosing and pharmacokinetic sampling scheme for ACT-1 and ACT-2. Open

circles and squares indicate treatment with infliximab 5 mg/kg or 10 mg/kg, respectively.

Figure S2. Distribution of infliximab concentrations among patients treated with infliximab 5 or

10 mg/kg in ACT-1 and ACT-2. CPW2, CPW6, CW8, CPW14, CPW30, and CPW54 (ACT 1 only)

represent serum infliximab concentrations at weeks 2, 6, 8, 14, 30, and 54, respectively; all preinfusion

with the exception of week 8. Box plots below show median (solid line in box), interquartile range

(upper and lower boundaries of box), mean (dotted line), and distribution of individual patient

concentrations (circles).

Figure S3. Proportion of patients achieving efficacy outcomes by serum infliximab concentration

quartiles in ACT-1 and ACT-2 for the 5-mg/kg treatment group at induction week 8 (A),

maintenance week 30 (B), and maintenance week 54 (C; ACT-1 only). The trend of the proportion of

patients achieving clinical outcomes across the quartiles was evaluated using the 1-sided Cochrane-

Armitage trend test.

Figure S4. Proportion of patients achieving clinical response by serum infliximab concentration

quartiles in ACT-1 and ACT-2 stratified by dose regimen at induction week 8 (A) and

maintenance week 30 (B). The trend of the proportion of patients achieving clinical outcomes across

the quartiles was evaluated using the 1-sided Cochrane-Armitage trend test.

Figure S5. The influence of serum infliximab concentration on subsequent efficacy outcome for

the combined 5- and 10-mg/kg infliximab doses. Median serum infliximab concentrations at weeks

30, 14, and 8 are shown for patients who did and did not achieve clinical remission at weeks 54 (ACT-1

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only), 30 , and 30, respectively (A-C) and proportions of patients in clinical remission at weeks 54

(ACT-1 only), 30, and 30 by serum infliximab concentration quartiles at weeks 30, 14, and 8,

respectively, among patients in remission at weeks 30, 8, and 8, respectively (D-F). For all panels, the 5-

and 10-mg/kg doses of infliximab are combined.

Figure S6. The influence of serum infliximab concentration on subsequent efficacy outcome by

infliximab dose. Median serum infliximab concentrations at week 30 are shown for patients who did

and did not achieve clinical remission at week 54 (ACT-1 only) for patients receiving infliximab

5 mg/kg (A) and 10 mg/kg (B) and proportions of patients in clinical remission at week 54 (ACT-1 only)

by serum infliximab concentration quartiles at week 30 among patients in remission at week 30 for

patients receiving infliximab 5 mg/kg (C) and 10 mg/kg (D).

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Week 0

Week 2

Week 6

Week 8

Week 14

Week 22

Week 30

Week 38

Week 42

Week 46

Week 54

Infliximab

5 mg/kg

(N = 121)

ACT-1

Infliximab

10 mg/kg

(N = 122)

Blood sampling (immediately before or 1 hour after infusion).

Infliximab

5 mg/kg

(N = 121)

ACT-2

Infliximab

10 mg/kg

(N = 120)

024

8_v2

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Infliximab 5 mg/kg

*ACT-1 only

Infliximab 10 mg/kg

2CPW

Infusion

n = 240 233 230 208 190 78 238 225 216 201 184 80

6 8 14 30 54* 2 6 8 14 30 54*

Seru

m inflix

ima

b c

on

ce

ntr

atio

n µ

g/m

L)

< 0.1

1

10

100

1000

10000

024

9

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Clinical

response

Mucosal

healing

Clinical

remission

0

20

40

60

80

100

Induction Week 8AP

rop

ort

ion

of

patie

nts

(%

)

02

50

_v2

Clinical

response

Mucosal

healing

Clinical

remission

0

20

40

60

80

100

Maintenance Week 30B

Pro

po

rtio

n o

f p

atie

nts

(%

)

02

51_v2

Clinical

response

Mucosal

healing

Clinical

remission

0

20

40

60

80

100

Maintenance Week 54C

Pro

po

rtio

n o

f p

atie

nts

(%

)

02

52

_v2

P < .001 P < .001

P < .05

P < .001 P < .0001

P < .0001

P < .001 P < .001

P < .01

< 21.3 µg/mL (n = 57)

21.3 to < 33.0 µg/mL (n = 58)

33.0 to < 47.9 µg/mL (n = 57)

≥ 47.9 µg/mL (n = 58)

0.1 µg/mL (n = 48)

> 0.1 to < 2.4 µg/mL (n = 47)

2.4 to < 6.8 µg/mL (n = 47)

≥ 6.8 µg/mL (n = 48)

< 1.4 µg/mL (n = 19)

> 1.4 to < 3.6 µg/mL (n = 20)

3.6 to < 8.1 µg/mL (n = 19)

≥ 8.1 µg/mL (n = 20)

52.6

69.0

75.481.0

45.6

56.9

71.9

79.3

26.3

37.943.9 43.1

47.953.2

76.672.9

43.844.7

83.0

75.0

14.6

25.5

59.6

52.1

31.6

70.0

94.7

75.0

36.8

65.0

94.7

80.0

21.1

55.0

79.0

60.0

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5 mg/kg

n = 57 58 57 58 54 54 54 54

0

20

40

60

80

100

Clinical Response at Week 8AP

rop

ort

ion o

f p

atie

nts

(%

)

02

53

_v5

10 mg/kg

5 mg/kg 10 mg/kg

52.6

69.075.4

81.0

50.0

68.5

79.685.2

n = 48 47 47 48 46 45 47 46

0

20

40

60

80

100

Clinical Response at Week 30B

Pro

po

rtio

n o

f p

atie

nts

(%

)

02

54

_v5

47.953.2

76.672.9

41.3

60.0

89.4 91.3

P < .0001P < .0001

P < .0001

P < .0001

< 2.2 µg/mL

2.2 to < 6.5 µg/mL

6.5 to < 15.8 µg/mL

≥ 15.8 µg/mL

0.1 µg/mL

> 0.1 to < 2.4 µg/mL

2.4 to < 6.8 µg/mL

≥ 6.8 µg/mL

< 44.4 µg/mL

44.4 to < 75.3 µg/mL

75.3 to < 101.4 µg/mL

≥ 101.4 µg/mL

< 21.3 µg/mL

21.3 to < 33.0 µg/mL

33.0 to < 47.9 µg/mL

≥ 47.9 µg/mL

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Me

dia

n in

flix

ima

b

co

nce

ntr

atio

n (

µg

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03

52

_v2

Infliximab Concentration at Week 14B

Me

dia

n in

flix

ima

b

co

nce

ntr

atio

n (

µg

/mL)

03

53

_v2

Infliximab Concentration at Week 8C

Me

dia

n in

flix

ima

b

co

nce

ntr

atio

n (

µg

/mL)

03

54

_v2

Proportion of Patients in Remission at Week 54

by Infliximab Concentration Quartiles at Week 30;

Patients in Remission at Week 30

D

% in R

em

issio

n a

t W

ee

k 5

4

03

55

_v4




E

% in R

em

issio

n a

t W

ee

k 3

0

03

56

_v4




F

% in R

em

issio

n a

t W

ee

k 3

0

03

57_v4

0

2

4

6

8

10

12

8.4

3.2

10.9

N = 85 N = 17 N = 68

Patients in

remission at

Week 30

Patients not in

remission at

Week 54

Patients in

remission at

Week 54

N = 21

<3.5

N = 21

3.5 to

<8.4

Infliximab concentration at Week 30 (µg/mL)

N = 21

8.4 to

<16.7

N = 22

≥16.7

0

2

4

6

8

10

12

N = 154 N = 52 N = 102

Patients in

remission at

Week 8

Patients not in

remission at

Week 30

Patients in

remission at

Week 30

N = 158 N = 54 N = 104

Patients in

remission at

Week 8

Patients not in

remission at

Week 30

Patients in

remission at

Week 30

8.2

5.1

10.1

0

10

20

30

40

50

60

70

49.0

41.0

59.0

0

20

40

60

80

100

52.4

P = 0.0046P = 0.0041

P = 0.0012

P = 0.0041

90.5 90.586.4

N = 38

<3.3

N = 39

3.3 to

<8.2


N = 38

8.2 to

<16.2

N = 39

≥16.2

0

20

40

60

80

100

P = 0.0010

N = 39

<32.1

N = 40

32.1 to

<49.0


N = 39

49.0 to

<89.6

N = 40

≥89.6

0

20

40

60

80

100

P = 0.0011

47.4

69.263.2

84.6

51.3

60.0

69.2

82.5

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5 mg/kg Treatment GroupA

Me

dia

n in

flix

ima

b

co

nce

ntr

atio

n (

µg

/mL)

04

25

Infliximab Concentration at Week 30

10 mg/kg Treatment GroupB

Me

dia

n in

flix

ima

b

co

nce

ntr

atio

n (

µg

/mL)

04

26

Proportion of Patients in Remission at Week 54 by

Infliximab Concentration Quartiles at Week 30; Patients

in Remission at Week 30 (5 mg/kg Treatment Group)

C

% in R

em

issio

n a

t W

ee

k 5

4

04

27

Proportion of Patients in Remission at Week 54 by

Infliximab Concentration Quartiles at Week 30; Patients

in Remission at Week 30 (10 mg/kg Treatment Group)

D

% in R

em

issio

n a

t W

ee

k 5

4

04

28

N = 41 N = 9 N = 32

Patients in

remission at

Week 30

Patients not in

remission at

Week 54

Patients in

remission at

Week 54

N = 10

<2.8

N = 10

2.8 to

<5.2


N = 10

5.2 to

<13.7

N = 11

≥13.7

N = 44 N = 8 N = 36

Patients in

remission at

Week 30

Patients not in

remission at

Week 54

Patients in

remission at

Week 54

0

20

40

60

80

100

N = 11

<7.2

N = 11

7.2 to

<12.1


N = 11

12.1 to

<18.1

N = 11

≥18.1

0

20

40

60

80

100

0

2

4

6

8

10

12

14

0

2

4

6

8

10

12

14

5.2

2.7

6.0

12.1

4.1

13.5

50.0

80.0

100.0

81.8

54.6

90.9

81.8

100.0

P = 0.0256

P = 0.0475

P = 0.0055

P = 0.0072

Association between serum concentration of infliximab and efficacy in adult patients with ulcerative...

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