Personalized Infliximab Induction Strategy With Model-informed Dosing in Patients With Crohn's Disease
Phase: PHASE2
Conditions: Crohn Disease
Sponsor: Children's Hospital Medical Center, Cincinnati

Personalized Infliximab Induction 
Strategy with Model-informed Dosing in 
Patients with Crohn’s Disease 
(REMODEL) 
Pilot & Feasibility 
Protocol IRB Number: 2020-0282 
National Clinical Trial (NCT) Identified Number: 
NCT04974099 
 
Principal Investigator: 
Phillip Minar, MD, MS – Cincinnati Children’s 
Hospital Medical Center 
 
Funded by:  
Crohn’s and Colitis Foundation 
Cincinnati Children’s Research Foundation (ARC) 
 
Version Number: 4 
14 Feb 2022 
 

 
 
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REMODEL 02.14.22 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 4 
1 
PROTOCOL SUMMARY ............................................................................................................................... 5 
1.1 
Synopsis ................................................................................................................................................ 5 
1.2 
Schedule of Activities (SoA) ............................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale .................................................................................................................................... 7 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits .............................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 12 
4 
STUDY DESIGN ........................................................................................................................................... 15 
4.1 
Overall Design .................................................................................................................................... 15 
4.2 
Scientific Rationale for Study Design.............................................................................................. 16 
4.3 
Justification for Dose ......................................................................................................................... 16 
4.4 
End of Study Definition ..................................................................................................................... 17 
5 
STUDY POPULATION ................................................................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................................................ 17 
5.2 
Exclusion Criteria ............................................................................................................................... 18 
5.3 
Lifestyle Considerations .................................................................................................................... 18 
5.4 
Screen Failures .................................................................................................................................. 18 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 18 
6 
STUDY INTERVENTION ............................................................................................................................ 19 
6.1 
Study Intervention(s) Administration ............................................................................................... 19 
6.1.1 
Study Intervention Description ..................................................................................... 19 
6.1.2 
Dosing and Administration ............................................................................................ 20 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 22 
6.2.1 
Acquisition and accountability ...................................................................................... 22 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 22 
6.2.3 
Product Storage and Stability ....................................................................................... 23 
6.2.4 
Preparation ...................................................................................................................... 23 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 24 
6.4 
Study Intervention Compliance ........................................................................................................ 24 
6.5 
Concomitant Therapy ........................................................................................................................ 24 
6.5.1 
Rescue Medicine ............................................................................................................ 24 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 24 
7.1 
Discontinuation of Study Intervention ............................................................................................. 24 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 25 
7.3 
Lost to Follow-Up ............................................................................................................................... 25 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 26 
8.1 
Safety and Feasibility Assessments ............................................................................................... 26 
8.1.1 
Definition of an AE ......................................................................................................... 26 
8.1.2 
Definition of a Serious AE ............................................................................................. 27 
8.2 
Pregnancy ........................................................................................................................................... 28 

 
 
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REMODEL 02.14.22 
8.3 
Recording of AE’s and SAE’s .......................................................................................................... 28 
8.3.1 
Recording and Evaluation of AEs ................................................................................ 29 
8.4 
Management of AEs .......................................................................................................................... 31 
8.4.1 
General ............................................................................................................................ 31 
8.4.2 
Management of Abnormal Laboratory Results .......................................................... 31 
8.4.3 
Pregnancy ....................................................................................................................... 31 
8.5 
Reporting of Serious AEs ................................................................................................................. 31 
8.5.1 
Investigator reporting ..................................................................................................... 32 
8.6 
Feasibility evaluation ......................................................................................................................... 32 
8.6.1 
Third Party Coverage .................................................................................................... 32 
8.6.2 
Physician Response to Dosing Recommendations .................................................. 33 
8.6.3 
Subject Adherence to Laboratory collections ............................................................ 33 
8.7 
Efficacy Assessments ....................................................................................................................... 34 
8.8 
Additional Assessments .................................................................................................................... 35 
8.9 
Unanticipated Problems .................................................................................................................... 37 
8.9.1 
Definition of Unanticipated Problems (UP) ................................................................. 37 
8.9.2 
Unanticipated Problem Reporting ................................................................................ 37 
8.9.3 
Reporting Unanticipated Problems to Participants ................................................... 37 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 38 
9.1 
Statistical Hypotheses ....................................................................................................................... 38 
9.2 
Sample Size Determination .............................................................................................................. 39 
9.3 
Populations for Analyses .................................................................................................................. 39 
9.4 
Statistical Analyses............................................................................................................................ 39 
9.4.1 
General Approach .......................................................................................................... 39 
9.4.2 
Analysis of Primary Aim EndpointS ............................................................................. 40 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 40 
9.4.4 
Baseline Descriptive Statistics ..................................................................................... 40 
9.4.5 
Planned Interim Analyses ............................................................................................. 40 
9.4.6 
Sub-Group Analyses ..................................................................................................... 41 
9.4.7 
Tabulation of Individual participant Data .................................................................... 41 
9.4.8 
Exploratory Analyses ..................................................................................................... 41 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 41 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 41 
10.1.1 
Informed Consent Process ........................................................................................... 41 
10.1.1.3 Study Discontinuation and Closure ................................................................................................. 43 
10.1.2 
Confidentiality and Privacy ........................................................................................... 43 
10.1.3 
Future Use of Stored Specimens and Data ............................................................... 44 
10.1.4 
Key Roles and Study Governance .............................................................................. 44 
10.1.5 
Safety Oversight ............................................................................................................. 45 
10.1.6 
Clinical Monitoring .......................................................................................................... 45 
10.1.7 
Quality Assurance and Quality Control ....................................................................... 46 
10.1.8 
Data Handling and Record Keeping ............................................................................ 46 
10.1.9 
Protocol Deviations ........................................................................................................ 47 
10.1.10 
Publication and Data Sharing Policy ........................................................................... 47 
10.1.11 
Conflict of Interest Policy .............................................................................................. 48 
10.2 
Additional Considerations ................................................................................................................. 48 

 
 
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REMODEL 02.14.22 
11 
REFERENCES ............................................................................................................................................. 48 
12 
APPENDICES: .............................................................................................................................................. 50 
 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following: 
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, 
and/or 21 CFR Part 812) 
 
The trial will be conducted in compliance with the requirements of 21 CFR 312.7, i.e., the drug 
may not be represented as safe or effective, nor may it be commercially distributed, for the 
purposes for which it is under investigation.   
 
The protocol, informed consent forms, recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. 
Approval of both the protocol and the consent form must be obtained before any participant is 
enrolled. Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study. In addition, all changes to the consent form will be 
IRB-approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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REMODEL 02.14.22 
 
1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Personalized Infliximab Induction Strategy with Model-informed 
dosing in Patients with Crohn’s Disease. 
 
Study Description: 
This is a Pilot study to evaluate safety, feasibility and efficacy of 
utilizing pharmacokinetic modeling to provide an individualized 
infliximab induction regimen in children and young adults with 
moderate to severe Crohn’s disease. This clinical study is designed 
with the hypothesis that treatment regimens that account for 
individual (patient) drug clearance (pharmacokinetic modeling) will 
not only be safe and cost-effective, but also more effective in 
reducing intestinal inflammation than as-labeled dosing (ALD) 
regimens. 
  
Objectives: 
 
Primary Objective: Obtain safety, feasibility and efficacy data for the 
optimal dosing strategy and sample size estimation to inform the 
design of a future, larger randomized controlled trial. 
 
 
 
Endpoints: 
Safety: Number of adverse and/or serious adverse events during the 
six-month study. 
 
Feasibility: Enrollment, study completion, clinician usability of 
dashboard and adherence (including the clinician and 3rd party 
insurance coverage) to dosing regimens recommended by the 
modeling program.  
 
Efficacy: (Primary) Rate of achieving infusion #3 (week-6) level in 
the target range (18-24 µg/ml).  
 
Study Population: 
20 male and female participants age 6 to 22 with Crohn’s disease 
who are scheduled to receive infliximab. 
 
Phase: 
II 
 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Cincinnati Children’s Hospital Medical Center 
 
Description of Study 
Intervention: 
 
Pharmacokinetic model-informed dosing recommendations are 
based on the subjects’ weight, serum albumin, erythrocyte 
sedimentation rate (ESR) and neutrophil CD64 activity ratio 
(nCD64). The dosing recommendations are presented to the 
clinician with the RoadMABTM dashboard system with the final 
dosing decision at the discretion of the treating physician.  

 
 
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REMODEL 02.14.22 
 
Study Duration: 
24 months 
 
Participant Duration: 
 
6 months 
 
 
1.2 SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screen 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Timeline (infusion) 
 
1 
 
2 
3 
4 
5 
6 
 
Weeks (range) 
 
0 
1 
2 
2-6 
10-14 
14-22 
18-30 
26-30 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility1  
X 
 
 
 
 
 
 
 
 
Demographics2 
X 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
X 
 
Surgical History 
X 
 
 
 
 
 
 
X 
 
Physical exam, weight3 
X 
 
 
 
 
 
 
X 
 
Record Clinical Lab Results4 
X 
X 
 
X 
X 
X 
X 
X 
 
Prior and Concomitant Medications5 
X 
X 
 
X 
X 
X 
X 
X 
 
Urine pregnancy test6 
X 
 
 
 
 
 
 
 
 
GI Symptoms Questionnaire7 
X 
X 
X 
X 
X 
X 
X 
X 
 
Provide dashboard dosing 
recommendations to MD8 
 
X 
 
X 
X 
X 
X 
 
 
Receive infliximab infusion9 
 
X 
 
X 
X 
X 
X 
X 
 
Blood collection10 
 
X 
X 
X 
X 
X 
X 
X 
 
Stool collection11 
--------X-------- 
 
 
X 
X 
 
X 
 
Coordinator calls12 
 
X 
 
 
 
X 
 
X 
 
MRI abdomen (MRE)13 
 
 
 
 
 
 
 
 
X 
Endoscopy severity score14 
X 
 
 
 
 
 
 
 
X 
Adverse events monitoring 
 
X 
 
X 
X 
X 
X 
X 
X 
1 Must meet full inclusion/exclusion criteria as described in protocol; includes males and females ages ≥6 year to ≤22 years 
old with prior diagnosis of Crohn’s Disease (CD), anti-TNF naïve, and starting infliximab (or infliximab biosimilar). 
2 Includes date of birth, date of diagnosis, gender, race, and ethnicity. 
3 Record measurements taken for clinical purposes. Includes weight, height and body mass index. Use the most recent 
results available. 
4 Will include all CD-related labs and those that will inform the infliximab model including serum albumin, ESR, nCD64, drug 
concentration, and antibody to drug concentration.  
5 All medications will be recorded.   
6 Urine pregnancy must be obtained prior to starting infliximab in all female subjects’ ≥12 years of age (or younger, if menses 
has begun).  
7 GI symptoms questionnaire assists in the completion of disease activity scoring and will be given prior to starting infliximab. 
The weighted Pediatric Crohn’s Disease Activity Index (clinical remission defined as wPCDAI<12.5) – combines subjective 
clinical evaluation (abdominal pain, stool frequency, and general well-being), and laboratory tests (albumin and ESR) with 
physical exam assessments (weight, perirectal disease and evaluation of extraintestinal manifestations). This will also 
include assessing patient reported outcomes as well.  
8 Patient weight and results of pertinent laboratory tests (serum albumin, ESR, nCD64, infliximab concentration, and 
antibody to infliximab concentration) will be input into the RoadMAB application. A print out with the dosing recommendation 
and expected PK dose/exposure curve will be supplied to the treating physician.  
9 Infusion schedule is listed in Figure2. The first 3 doses (induction) are standardized at 0, 2 and 6 weeks. The maintenance 
regimen (infusion4 and subsequent infusions) will be determined and then ordered by the treating physician.  

 
 
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REMODEL 02.14.22 
10 All attempts will be made to avoid research-only visits.  Instead, sample collection will be planned to coincide with 
previously scheduled infusion visits, except V2, which occurs at week1 and is optional. V2 is a lab-only visit to obtain 
infliximab concentration, a complete blood count, ESR, nCD64 and hepatic profile.  The volume of blood obtained will follow 
guidelines for children – the lesser of 3ml/kg or maximum of 20ml collected for research purposes. 
11 All subjects will collect stool at home and either mail the sample directly to the Minar Laboratory or bring the stool sample 
to the infusion visit. A total of 4 stools will be collected (screening or infusion 1 and infusions 3, 4, and 6) 
12 Coordinator calls are scheduled to evaluate for any AE or SAE and to remind participants of upcoming infusion visits.  
13 Participants will be asked to have an optional MRI scan (using oral contrast, Breeza®, or water) at V8 (approximately 
weeks 26-30) 
14 Endoscopy scoring is NOT feasible for this pilot study. However, if the participant has a colonoscopy six months prior to 
study enrollment or at any during the study period, we will perform the Simple Endoscopic Severity-Crohn’s disease (SES-
CD) from the video-recordings (if available with the CCHMC vaultstream application).  
 
 
2 
 
INTRODUCTION 
 
2.1 STUDY RATIONALE  
Approximately 3 million people (including >100,000 children) in the United States are living 
with inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis 
(UC).1 Despite advances with novel treatments, many children and adults with IBD continue to 
experience significant gastrointestinal symptoms (disease flares) and preventable disease 
complications.  
Therapeutic targets for CD include monoclonal antibodies (mAb’s) that antagonize 
circulating and tissue-bound inflammatory cytokines (anti-TNF, anti-IL12/23) and leukocyte 
recruitment pathways (anti-integrin). For pediatric CD, the Food and Drug Administration (FDA) 
has approved two anti-TNF mAb’s, infliximab (and infliximab biosimilars) and adalimumab for 
children (>6 years old) with moderate to severe CD. Infliximab (anti-TNF) remains the most 
commonly used first-line biologic agent for children with moderate to severe CD. Infliximab was 
first FDA-approved for children (6-17 years old) with moderate to severe CD based on the results 
of the pivotal REACH study.2 Based on this study2, infliximab dosing occurs in two phases, 
induction and maintenance. The induction dose is 5 mg/kg at 0, 2 and 6 weeks. The maintenance 
dosing regimen is 5 mg/kg every 8 weeks, which is the same dosing regimen approved for adults 
(>18 years old) with IBD.3,4 
Although the rates of initial clinical response to anti-TNF dosing regimens as-labeled 
exceed 80%2, 3, rates of complete intestinal (bowel) healing only range between 36-46% with 
merely 19-36% of patients on maintenance therapy able to achieve deep remission (a therapeutic 
target that includes the combination of clinical remission and intestinal healing).4, 5 For most 
patients, failure to achieve deep remission is directly related to (1) subtherapeutic drug exposure 
(both during induction and maintenance phases) or (2) the development of neutralizing anti-drug 
antibodies in the setting of low drug concentrations.6 Moreover, in a pediatric study of 955 children 
receiving infliximab, the authors found the only predictors of non-remission at one year were 
subtherapeutic drug concentrations at week 14 (end of induction) and development of 
antibodies to infliximab.7 As a result, there are intensified efforts for tighter and earlier control 
of the inflammatory burden by providing individual patients with optimized drug exposure 
during induction7 and maintain the targeted drug exposure through the reliable use of 
proactive therapeutic drug monitoring (pTDM) and subsequent dose optimization.4  
Based on a large CD cohort who provided longitudinal biosamples to produce a real-world 
pharmacokinetic (PK) model, our team has developed an innovative physician support dashboard 
for infliximab (RoadMABTM). RoadMABTM utilizes our population PK model that includes novel 
biochemical covariates (weight, albumin, ESR and nCD64) to estimate infliximab clearance to 
provide personalized dosing regimens for patients starting infliximab. Therefore, we hypothesize 

 
 
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REMODEL 02.14.22 
that model-informed infliximab dosing that accounts for individual drug clearance with routine 
blood biomarkers to inform the starting infliximab dose will more accurately achieve the targeted 
drug exposure during induction than as-labeled dosing (ALD). 
 
2.2 BACKGROUND  
The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), 
affect an estimated 3 million people in the United States,1 including approximately 100,000 
children and adolescents. The peak age of onset for pediatric CD is early adolescence with a 
rising incidence of children diagnosed with IBD before 10 years of age.8 With the early age of 
onset, pediatric patients are susceptible to prolonged intestinal damage resulting in growth failure, 
intestinal strictures with possible bowel obstruction and significant penetrating complications 
(fistula or abscess formation).9, 10 In a cohort of 989 newly diagnosed pediatric CD patients, 38% 
developed a CD-related complication within the first 10 years of diagnosis.11  
Therapeutic options for moderate to severe CD include monoclonal antibodies (mAb) that 
antagonize circulating or tissue-bound inflammatory cytokines and leukocyte recruitment 
pathways. Following the pivotal REACH study,2 mAb’s targeting tumor necrosis factor-alpha (anti-
TNF) are the most commonly used first-line biologic agents for children with moderate to severe 
CD. Although high rates of early (week 10) clinical response to anti-TNF are reported (75-
88.4%),2, 3 many children and adults continue to experience symptom flares and serious disease 
complications as long-term rates of mucosal healing range between 36-46% with only 19-36% 
achieving deep remission5 ,The variation in treatment response likely reflects the heterogeneity of 
CD phenotypes, the individual differences in location and extent of inflammation and patient-
specific cytokine burden. Despite this heterogeneity of disease and significant differences in drug 
clearance,12, 13 initial infliximab dose selection during induction is solely based on the patient’s 
weight and not on readily available biomarkers that can accurately predict drug clearance.2, 14 
Although infliximab is FDA-approved for children (ages 6-17 years) with moderate to severe 
CD, there is significant evidence that utilizing the labeled infliximab dosing schedule of 5 mg/kg 
at 0, 2 and 6 weeks (induction) followed by infusions at 5 mg/kg every 8 weeks (maintenance) 
results in subtherapeutic drug concentrations, a 20-25% rate of immunogenicity and poor drug 
durability in children with CD.12, 15-17  
Current as-labeled infliximab dosing regimens were developed prior to the routine use of 
therapeutic drug monitoring (TDM) and without knowledge of a well-characterized dose-
exposure-response relationship. Therefore, subtherapeutic infliximab concentrations are common 
as availability of biomarkers to predict rapid infliximab clearance for either dose selection (starting) 
or dose optimization strategies are lacking. In fact, we found that 59% of patients receiving the 
aforementioned ALD infliximab regimens had subtherapeutic drug concentrations prior to the third 
induction dose.12 In a recent retrospective review comparing outcomes between adults IBD 
patients who received reactive TDM (rTDM) vs. pTDM, patients with pTDM had higher rates of 
drug durability and a decrease in IBD-related surgery, hospitalizations, immunogenicity and 
infusion reactions.6  

 
 
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REMODEL 02.14.22 
Moreover, in our longitudinal cohort of anti-naïve CD patients receiving infliximab 
induction, treatment response (clinical and biochemical) was associated with a higher infliximab 
concentration (Figure1a-b)12 and infliximab exposure (Figure 1c, unpublished). We subsequently 
developed 
a 
real-world 
population 
PK 
model 
for 
infliximab with our CD cohort and 
found that drug clearance was 
affected by patient weight, serum 
albumin, antibody to infliximab 
(ATI), ESR, nCD64 and use of 
prednisone (Table1).  
These data support the 
hypothesis that model-informed 
infliximab dosing that accounts 
for individual drug clearance with 
routine blood biomarkers to inform the starting infliximab dose will more accurately achieve the 
targeted drug exposure during induction than ALD. 
As noted, several treatment strategies to maximize outcomes to anti-TNF have developed 
and include rTDM,18 pTDM,6, 19 and treatment to target.4 With our trial design, we are not only 
testing whether personalized dose selection will improve short-
term and six-month outcomes, we are also testing the feasibility 
and usability of a Precision Dosing Dashboard, RoadMABTM. 
The RoadMABTM Dashboard is a real-time decision support 
system that incorporates PK model-informed Bayesian 
estimation to provide precision dosing at the point of care. 
Briefly, RoadMABTM extracts patient data (weight, concurrent 
medications and blood biomarker results) from the electronic 
medical record (EMR) and produces individual PK profiles to 
accurately predict drug exposure between infusions. The 
RoadMABTM user-interface is intuitive and provides a visual 
snapshot of the predicted drug concentration (trough) at the 
next infusion. For this pilot study, the Dashboard will provide 
the starting dose with each patient set to receive the ALD 
induction intervals at 0, 2 and 6 weeks. During maintenance, 
the Dashboard can then be utilized for both infliximab dosing 
and interval (weeks) selection.  
Our approach will have a high impact in the field by 
providing critical safety and efficacy data along with implementation strategies to support a future 
clinical trial. Utilizing the results of this pilot investigation, our long-term goal is to conduct a 
comparative effectiveness clinical trial to evaluate short and long-term efficacy outcomes between 
patients receiving a personalized induction regimen with treatment to target (blood biomarkers) 
dose intensifications using RoadMABTM in comparison to patients receiving ALD infliximab 
regimens. 
 
2.3 RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
The risks associated with this study are associated with infliximab (or infliximab biosimilar), 
venipuncture, magnetic resonance imaging (MRI) and breach of confidentiality.  

 
 
Page 10 of 50 
REMODEL 02.14.22 
 
Infliximab: Safety and efficacy of infliximab has been established in pediatric (>6 years old) 
and adult-onset CD patients.2, 20, 21 There is a relative paucity of dose-exposure risks with 
infliximab.22 However, risks with high dose infliximab could include:   
• 
elevation of liver enzymes 
• 
infection 
 
Venipuncture: Every attempt will be made for whole blood collection to coincide with intravenous 
catheter placement and therefore, will be no additional risks from breaches of the skin with a 
needle.  However, for some study participants, research-only venipuncture will occur. To reduce 
the risks (pain, bleeding, infection, and bruising), we will limit the number of venipunctures to 
obtain the blood sample to two attempts. Blood will be collected by persons experienced in 
drawing blood from infants and children. There is a very small additional risk of syncope 
associated with phlebotomy. Known risks associated with peripheral blood sampling are: 
• 
pain 
• 
bruising 
• 
fainting (rare) 
• 
infection (rare) 
 
MRI: MRI is generally considered to be a safe, noninvasive diagnostic imaging modality. Known 
and potential discomforts or hazards, as stated in the suggested guidelines for the operation of 
clinical MRI systems established by the FDA, are associated with static magnetic field, 
radiofrequency magnetic field, and gradient magnetic field. The MRI scanning may induce few, if 
any, tangible risks in this study.  
 
The 1.5T static magnetic field strength of the MRI scanner is below the 4.7T limit for clinical 
diagnostic MRI scanners set by the FDA guidelines. The FDA has concluded that magnetic field 
below 4.7T does not by itself impose a risk to human subjects. In short, the FDA has approved 
the use of magnetic field strengths of up to 4.1T for MRI scanning of humans in the research 
environment. While there is no biohazard associated with exposure to static magnetic fields, there 
are safety concerns related to ferromagnetic attraction.  
 
The radiofrequency magnetic field used in MRI can induce heating in the subject. 
 
The gradient magnetic field can induce peripheral nerve stimulation in the subject if the rate of 
change of the gradient magnetic field is too high. 
 
The use of gradient magnetic fields generates MRI scanner noise. This noise level is dependent 
on the rate of change of gradient magnetic field in a given pulse sequence. Discomfort may occur 
due to noise produced by the MRI scanner.  
 
Oral contrast for the MRI will be used. This includes, but may not be limited to, Breeza®, a flavored 
beverage that is necessary to evaluate bowel inflammation for patients with CD. Breeza® is 
sugar-free, gluten-free and generally considered safe (manufactured by Beekley Corporation, 
Bristol CT). Breeza® does contain sorbitol and mannitol which may cause diarrhea in some 
patients. 
 
Known risks associated with MRI are: 
• 
scanner (loud) noise 
• 
ferromagnetic attraction 

 
 
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REMODEL 02.14.22 
• 
diarrhea from oral contrast 
2.3.1.1 ADEQUACY OF PROTECTION AGAINST RISKS: 
 
The risks associated with MRI scanning will be addressed with the following actions: 
Subjects will undergo routine screening to determine if there is any contraindication to MRI. 
Assuming there is no contraindication, the planned research MRI protocol is without known risk. 
Standard MRI procedures will be followed to minimize injury risk due to ferromagnetic projectile 
object(s). 
 
MRI scanning will be performed using techniques that are substantially similar to techniques used 
to image other non-bowel parts of the body. FDA limits for dB/dT, specific RF absorption rate 
(SAR) and acoustic noise will not be exceeded.  
 
1.5T and 3T magnets are approved by the FDA. There is no known biohazard associated with 
short-or long-term exposure to its magnetic field strength. MRI of the abdomen and pelvis is 1.5T 
or 3T is commonly performed at CCHMC in children of all ages and adults. The safety of MRI, 
particularly with respect to the lack of ionizing ration, is well-known. 
 
The MRI scanner will be operated by certified technologists that have been trained to properly 
use the MRI scanner. These technologists also undergo training in the proper conduct of 
research. 
 
The safety hazard associated with the attraction of ferromagnetic objects in the MRI environment 
is well-known in the radiology community and safety programs have been created to train 
individuals how to remain safe in this environment. MRI safety training will be required for all 
clinical and support staff participating in this study. Additional safety precautions include subject 
questionnaires and interviews 
 
FDA guidelines regarding SAR require that the subject’s core temperature rise be less than 1 
degree Celsius. In the absence of core temperature monitoring equipment, the manufacturers 
have continued to use the previously established FDA limits of 2 W/Kg (average) and 8 W/Kg 
(peak). The system limits the SAR to levels at or below the conservative FDA limit for routine 
imaging applications: 1 W/Kg. In order to monitor this value, the RF energy at the output of the 
amplified is measured over a period of 10 seconds. In addition to the average output power, the 
peak value is also monitored. In the event that one of these values is exceeded, the transmitter 
power supply is turned off automatically within 3 to 5 seconds. These measures ensure that the 
system is well within the current FDA regulations on SAR.  
 
The FDA suggested limit for the rate of change of magnetic field (dB/dt) is 20T/sec. This 
conservative limit is maintained by the system on all three gradients. The scanner measures the 
gradient currents in time steps of 100 microseconds. In the event that the maximum allowed 
values are exceeded, a signal is given to the operator console, and the scan cannot be initiated. 
The operator must reduce the gradient strengths by increasing the slice thickness and/or reducing 
acquisition matrix sizes before the scan can proceed.  
 
Ear plug and/or earmuffs will be used for sound isolation based on institutional protocols.  
 
Breeza® will not be given to any participants with a known allergy to any of the labeled ingredients.  
 

 
 
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REMODEL 02.14.22 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Based on results of previous studies, subtherapeutic levels of infliximab during induction 
were found to be strongly associated with early and late treatment failure.7, 12, 16, 23 Therefore, 
personalized dose selection utilizing the individual patients inflammatory burden (assessed 
with blood biomarkers) and PK modeling may not only increase the rate of treatment 
response during induction, but optimized dosing may also improve drug durability by 
sustaining adequate drug exposure and minimizing the development of neutralizing 
antibodies.   
 
Results of this study will provide invaluable data regarding whether model-informed dosing of 
infliximab is safe, feasible and effective at obtaining the targeted exposure during therapy. 
This knowledge will inform the design and sample size of a future, larger comparative 
effectiveness clinical trial. This new knowledge will be utilized to improve clinical practice. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
We anticipate that the risks that participants will be exposed to during this study will be mild to 
moderate. 
 
The study will mitigate risks related to model-informed infliximab dosing by assembling 
experienced gastroenterologists who are familiar with the profile of adverse events in this 
patient population to oversee the study (Medical Monitor). 
 
Risks related to venipuncture will be mitigated by ensuring the activity is performed by 
expert personnel who are experienced in the care of pediatric patients. 
 
The potential benefits of study participation outweigh the potential risks to participants. 
 
 
3 
OBJECTIVES AND ENDPOINTS 
Table2: Primary and secondary outcomes 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Obtain data regarding 
safety and feasibility 
for the optimal dosing 
strategy to test in a 
future, larger clinical 
trial 
 
SAFETY: 
Adverse events (infusion 
reactions, rate of infections, 
and/or progression of 
gastrointestinal symptoms) 
and other possible drug 
reactions will be recorded 
and provided to the 
medical monitor.  
The FDA-approved dosing 
schedule during induction and 
maintenance has been shown to be 
safe and effective for the treatment 
of pediatric CD (>6 years old). 
Doses >5 mg/kg up to <15 mg/kg 
every 4-8 weeks (during 
maintenance) are safe.24, 25 Doses 
>15 mg/kg every 4 weeks or >20 

 
 
Page 13 of 50 
REMODEL 02.14.22 
Table2: Primary and secondary outcomes 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
 
 
 
FEASIBILITY: 
Enrollment and completion: We 
will evaluate the rate of 
recruitment including the 
number of patients that 
complete the study. We will 
evaluate the rate of patient 
adherence to stool and blood 
sample collections. 
 
Usability: RoadMAB will 
generate recommended 
starting doses (mg/kg) during 
induction along with doses and 
dosing intervals during 
maintenance. We will evaluate 
rate of physician adherence to 
this recommendation along 
with explanation for non-
adherence. We will also record 
3rd party payer denials for 
recommended doses and/or 
dose intervals.  
 
EFFICACY:  
Primary: 
Rate of achieving infus3 (V4) 
infliximab concentration 
between 18-24 µg/ml as a 
dichotomous outcome.  
 
 
 
 
 
 
 
 
mg every 6 weeks were found to be 
associated with an increased risk of 
adverse events.22   
 
 
The pilot study will provide valuable 
information for patient recruitment 
strategies and methods to assure 
adherence to biospecimen 
collection. 
 
 
 
 
Insurance coverage for higher 
doses is variable and dependent on 
multiple factors. Prior to conducting 
a larger clinical trial, this pilot will 
inform strategies for future 
coverage of medication costs.  
 
This pilot study will provide 
additional opportunities for the 
RoadMAB Dashboard design team 
to better understand physician 
prescribing practices and 
opportunities to distribute evidence 
based practices.  
 
We have recently published 
infliximab induction targets that 
were associated with therapeutic 
trough values at the first 
maintenance dose.12 The primary 
efficacy endpoint for the pilot is to 
investigate the accuracy of the 
Dashboard to achieve the desired 
drug exposure as well as rates of 
biochemical remission in patients 
receiving optimized drug exposure. 
 

 
 
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REMODEL 02.14.22 
Table2: Primary and secondary outcomes 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Secondary 
 
 
Evaluate the accuracy 
of infliximab 
concentration targets 
EFFICACY:  
Secondary: 
1. Median difference of infus3 
(V4) levels between cases and 
controls (historic controls that 
were previously enrolled and 
received ALD infliximab during 
induction. 
 
2. Incidence of achieving infus2 
(V3) level between target range 
of 26-34 µg/ml as a 
dichotomous outcome.  
 
3. Median difference of infus2 
(V3) levels between cases and 
controls. 
4. Rates of achieving 
maintenance targets infus4-6 
(V5-7) between 5-10 µg/ml. 
5. Rate of development of anti-
infliximab antibodies at any 
infusion between cases and 
controls. 
6. The proportion of patients in 
clinical response and remission 
at infus4 (V5) and infus6 (V7). 
 
Clinical response: 
improvement in baseline 
wPCDAI by >17.5 or a 
wPCDAI<12.5 
Clinical remission (CR): 
wPCDAI <12.5 and off 
corticosteroids. 
 
7. Rate of sustained remission: 
wPCDAI <12.5 and off 
The results of these outcomes will 
provide sample size and power 
calculations for our future trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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REMODEL 02.14.22 
Table2: Primary and secondary outcomes 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
prednisone for all visits from 
infus4 (V5) to infus6 (V7). 
 
8. The proportion of patients in 
biochemical response and 
remission at infus4 (V5) and 
infus6 (V7) 
 
Fecal calprotectin response: 
≥50% improvement in fecal 
calprotectin.26 
Fecal calprotectin remission: 
fecal calprotectin <250 µg/g. 
 
9. Rate of transmural ileal, 
colonic and total bowel healing 
at infus6 (V7) by MRI. 
 
Ileal healing: ileum subscore 
stage 0 (score = 0)  
Colonic healing: all segments 
of colon subscore stage 0 
(score = 0).  
Total bowel healing: total 
ileum and colonic subscore is 
not greater than stage 0 on 
either individual score.  
 
4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
We hypothesize that model-informed infliximab dosing that accounts for individual drug clearance 
with routine blood biomarkers to inform the starting infliximab dose will more accurately achieve 
the targeted drug exposure during induction than ALD in patients with moderate-to-severe 
Crohn’s disease.  
To test this hypothesis, we will conduct a prospective, single-center pilot study. This study will 
primarily include the intervention cohort. This cohort includes patients, age 6-22 years old who 
have been diagnosed with CD, are naïve to anti-TNF medications and are scheduled to start 
infliximab (or infliximab biosimilar).  
 

 
 
Page 16 of 50 
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In order to test additional (secondary) outcome measures, this study will also include an 
observation (comparison) cohort. This cohort includes patients (age 6-22 years old) who were 
diagnosed with CD, were anti-TNF naïve and have previously received ALD (5 mg/kg) infliximab 
during induction at CCHMC (IRB 2016-2046; 2017-1987). Additionally, this comparison cohort 
has had biospecimens (blood and stool) previously collected to compare drug concentration levels 
along with the various clinical and biochemical treatment outcomes.  
 
The intervention includes utilizing Clinical and Patient Decision Support Software (RoadMABTM) 
that will guide the selection of the first infliximab dose followed by subsequent infliximab dose 
and dosing interval during the maintenance phase.  
 
During induction, three infusions will occur at 0, 2 and 6 weeks, respectively. The RoadMABTM 
dashboard will utilize PK modeling software to provide an infliximab starting dose 
recommendation (range of 5-12 mg/kg) based on the patients biochemical profile (weight, serum 
albumin level, sedimentation rate [ESR], neutrophil CD64 activity ratio [nCD64] and prednisone 
exposure). For RoadMABTM to perform the most accurate dose calculation with Bayesian 
estimation, a minimum of patient weight, baseline serum albumin and nCD64 will be required for 
this study. As noted, dosing frequency (weeks) during induction will not be altered during this 
study. 
  
For dose selections following induction (maintenance phase), we have found therapeutic targets 
are more reliably achieved when all covariates (weight, nCD64, serum albumin and presence of 
drug antibodies) are available. RoadMABTM, however, utilizes only available data to formulate a 
dose recommendation (it does not impute missing data). Following the first three doses, the 
clinician will be informed of their patients PK profile within the RoadMABTM program and with a 
shared document (paper). RoadMABTM will provide additional dosing recommendations after each 
infusion (based on the latest drug concentration measures and blood biomarkers) with the final 
dose and interval selected by the treating physician.   
As the treating physician may alter dose and frequency for a number of reasons, an important 
endpoint is the rate the treating physician utilizes the Dashboard’s dosing recommendation with 
further documentation to be recorded for reasons of non-adherence.  
Every effort will be made to have the study visits coincide with a clinic visit or an infliximab infusion. 
If this is not possible, the subject will be seen at the Schubert Research Clinic (SRC), located on 
the first floor of the Clinical Sciences Pavilion (Location T.) Visit 2 and Visit 8 are optional 
research-only visits and not paired with a clinical infusion.  
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This is one of the first studies to utilize population PK and blood biomarkers to inform the starting 
dose of infliximab. The study design is in response to multiple studies finding that early treatment 
response and maintenance of response to infliximab is strongly associated with infliximab 
exposure during induction.7, 12, 27  
These studies will have a high impact in the field by providing critical safety and efficacy data. In 
addition, this pilot study will inform the sample size calculation for a comparative effectiveness 
trial to test the short and long-term efficacy of personalized dosing regimens.   
 
4.3 JUSTIFICATION FOR DOSE 
 

 
 
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The current FDA-approved infliximab dosing schedule for induction (first 3 doses) is 5 mg/kg given 
at 0, 2 and 6 weeks. For patients with severe disease (significant inflammatory burden, low serum 
albumin), doses up to 20 mg/kg have been utilized.2, 22, 28, 29 Previous data has repeated shown 
that infliximab 5 mg/kg during induction results in significant subtherapeutic levels in pediatric 
CD,12, 30 while physicians routinely utilize patient biomarkers such as serum albumin to 
individualize treatment regimens to account for increased drug clearance in clinical practice. In 
fact, in our real-world infliximab PK study with 66 CD patients enrolled, only 33.3% of those 
enrolled received the ALD induction regimen (not published). The median starting infliximab dose 
was 6 mg/kg with a range (min-max) of 4.1 to 12.1 mg/kg. 
 
However, empiric (off-labeled) dosing without consideration of individual drug clearance that PK 
modeling can provide may increase the risk of developing supra-therapeutic concentrations with 
a relative increase in the risk of adverse events.22 Although influenced by a single patient, Hendler 
et al. found that doses >2.5 mg/kg/week (such as >15 mg/kg every 4 weeks or 20 mg/kg every 6 
weeks) was associated with a higher rate of a serious infection.22  
 
Importantly, based the available safety data for off-labeled infliximab dosing,22 the RoadMABTM 
Dashboard is enhanced to only provide dosing recommendations that range from 5-12.5 mg/kg 
with rounding up to the nearest 100 mg (each infliximab vial is supplied as 100 mg). The PI will 
oversee each prescribed regimen to ensure compliance with this recommendation.  
 
4.4 END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all study visits 
including the last study visit as shown in the Schedule of Activities (SOA, Section 1.2.) or has 
discontinued infliximab before week 26.  
 
5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Written informed consent form from the patient (≥18 years old) or from parent/legal 
guardian if patient is <18 years old. 
2. Written informed assent form from patient ≥11 years old.  
3. Age criteria: ≥6 years to ≤22 years of age. 
4. Diagnosis of Crohn’s Disease 
5. Starting infliximab (or biosimilar)  
6. Anti-TNF naïve (never received infliximab, adalimumab, golimumab, certolizumab or anti-
TNF biosimilar) 
7. Fecal calprotectin >250 µg/g or fecal lactoferrin >10 µg/g (up to 6 weeks prior to starting 
infliximab) or endoscopic evidence of active Crohn’s disease (up to 90 days prior to 
starting infliximab) 
8. wPCDAI >12.5 (up to 6 weeks) prior to the first infliximab infusion 
9. Negative urine pregnancy test for ALL female subjects 
10. Negative TB (tuberculosis) blood test  
 
 

 
 
Page 18 of 50 
REMODEL 02.14.22 
5.2 EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Diagnosis of ulcerative colitis or inflammatory bowel disease-unspecified 
2. Prior treatment with infliximab, adalimumab, certolizumab or golimumab (or anti-TNF 
biosimilar) 
3. Active or prior evidence in past 12 months of internal (abdominal/pelvic) penetrating 
fistula(e) 
4. Active intestinal stricture (luminal narrowing with pre-stenotic dilation >3mm), intra-
abdominal abscess or perianal abscess 
5. Active Clostridium difficile infection or other known bacterial/viral gastroenteritis in last two 
weeks 
6. Current ileostomy, colostomy, ileoanal pouch, and/or previous extensive small bowel 
resection leading to short bowel syndrome 
7. History of autoimmune disease (including autoimmune hepatitis, primary sclerosing 
cholangitis, thyroiditis, psoriasis or juvenile idiopathic arthritis) 
8. Treatment with another investigational drug within four weeks. 
9. Treatment with intravenous antibiotics within four weeks. 
10. Planned continuation of 6-mercaptopurine or azathioprine (Imuran) during study. 
11. Planned continuation of methotrexate during study. 
12. Treatment with intravenous corticosteroids within two weeks. 
13. Currently pregnant, breast feeding or plans in next 12 months to become pregnant 
14. Inability or failure to provide informed assent/consent 
 
5.3 LIFESTYLE CONSIDERATIONS 
 
None.  
 
5.4 SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but do 
not receive the study intervention. In order to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities, the 
following information about screen failures will be collected:  
• 
Demographics 
• 
Reason for being defined as a screen failure  
• 
Any serious adverse event (SAE) 
 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
Subjects meeting Inclusion/Exclusion Criteria will be enrolled from the CD population served by 
CCHMC.  CCHMC provides care to >800 children and young adults with IBD. The CD population 
is approximately 520 patients. Over the last 5 years, our center has diagnosed 50-63 CD patients 
each year.    

 
 
Page 19 of 50 
REMODEL 02.14.22 
Over the last year (2019), approximately 60 CD started infliximab. We anticipate that 
approximately 50-75% of eligible subjects would agree to participate, providing a pool of >20 
subjects per year. We anticipate enrollment will be complete in two years.  
Patients who meet these inclusion criteria may be identified from multiple reports. Each week, the 
IBD team of physicians performs population management through ImproveCareNow (ICN). 
Patients are also identified by the nurse (RN) and medical assistant (MA) assigned to all new 
biologic (anti-TNF) starts for insurance prior-authorizations. Finally, the research team is also 
notified of potential study participants by the team members (administrative assistants) who 
schedule each infliximab infusion at our center (Burnet and Liberty campuses).  
All eligible patients will then be contacted at clinic visits or by phone to discuss study participation 
before they start infliximab (or infliximab biosimilar).  We anticipate enrolling 1-2 patients per 
month and therefore completing enrollment over 24 months, allowing for up to 10% drop-out.  The 
anticipated racial and ethnic composition will reflect the demographic characteristics of CD 
patients at CCHMC.  Children are considered to be vulnerable populations due to being unable 
to provide consent for their participation.  To mitigate this, we will seek their assent to participate 
if ≥11 years old.  
The study coordinators will contact the patients by phone prior to each required study visit. 
The study will provide a compensation for participation in the study as detailed below: 
• 
Visit 1: $40 
  
• 
Visit 2: $25 
• 
Visit 8: $75 (includes optional MRI) 
• 
Each infusion laboratory collection: $15 for the infusion visit 
• 
Each stool sample provided (up to 4): $25 each. 
 
Potential Problems and Alternative Approaches.  Over 500 CD patients are cared for at 
CCHMC and the concept of personalized dosing to maximize efficacy is wanted not only by 
physicians to improve outcomes19, but is also desirable to CD patients.  Therefore, the study is 
not likely to be limited by low enrollment.  However, if enrollment goals are not being met, we can 
consider adding additional pediatric academic centers including Nationwide Children’s Hospital 
or Connecticut Children’s Medical Center based on the PI’s previous research collaboration with 
these centers. 
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Infliximab is a recombinant chimeric immunoglobulin (Ig)G1 monoclonal antibody (mAb) that 
neutralizes the biologic activity of soluble and membrane-bound tumor necrosis factor-α (TNF) 
and is conventionally dosed at 5 mg/kg at 0, 2, and 6 weeks during induction followed by 5 mg/kg 
infusions every 8 weeks during maintenance.31 Despite the universal practice of weight-based 
dosing (starting at 5 mg/kg) at routine intervals, there are limited infliximab PK and 
pharmacodynamic (PD) studies in children.13 Moreover, studies have found that >50% of patients 

 
 
Page 20 of 50 
REMODEL 02.14.22 
will require a dose intensification (empiric dose adjustments up to 10-15 mg/kg) to maintain 
therapeutic efficacy.31, 32 
 
We and others have found children frequently require dose intensifications (both dose and dose 
interval) to maintain steroid-free clinical remission and to reduce drug immunogenicity (auto-drug 
antibodies).14, 19, 30 There is emerging evidence that personalized dosing regimens informed by 
pTDM to assess individual drug clearance leads to improved long-term outcomes by prolonging 
drug durability.6 Therefore, the prevalence of pediatric and young adult CD patients receiving “off-
label” infliximab dosing regimens to maintain target drug concentrations continues to increase.14   
 
The study intervention includes utilizing Clinical and Patient Decision Support Software 
(RoadMABTM Dashboard) to guide the selection of the first induction dose to accurately achieve 
a 3rd dose (week 6) drug concentration between 18-24 µg/ml and subsequently provide 
maintenance dose and dosing interval recommendations to sustain infliximab concentrations 5-
10 µg/ml following induction.33, 34 
6.1.2 DOSING AND ADMINISTRATION  
 
As noted, the starting FDA-approved dose for infliximab is 5 mg/kg. We and others have found 
ALD greatly underestimates individual drug clearance. Therefore, this study will look to optimize 
infliximab exposure with personalized dosing recommendations.  
 
Briefly, the RoadMABTM Dashboard is a real-time decision support system that incorporates the 
population PK model with Bayesian estimation to achieve personalized dosing regimens at the 
point 
of 
care 
with 
a 
PK 
software 
program 
(MWPharm++, 
MEDIMATICS, 
http://www.medimatics.net/projects/mwpharm). In contrast to off-label dosing schemes informed 
by 
“expert-opinion,” 
Bayesian 
systems 
select 
an 
optimal 
starting 
dose 
to 
achieve the targeted 
concentration for an 
individual patient. As 
the 
targeted 
concentration changes 
during 
induction 
as 
compared to the maintenance phase, RoadMABTM will provide dosing recommendations at four 
time points during this study (as shown in Figure2).   
 
Infliximab clearance has been shown to be influenced by the patients weight, serum albumin, 
ESR, nCD64, prednisone use and the degree of antibody to infliximab concentration.14 With these 
aforementioned covariates entered into the dashboard, RoadMABTM provides the clinician with a 
graphic display of up to three dosing regimens and the subsequent predicted infusion3 drug 
concentrations (Figure3, below). Additionally, the clinician can also toggle through other infliximab 
doses and visualize the predicted drug concentration. For this study, the infliximab target 
concentration during induction is 18-24 µg/ml prior to the 3rd dose and 5-10 µg/ml prior to 
each maintenance dose.7  
 

 
 
Page 21 of 50 
REMODEL 02.14.22 
Timing of TDM and utilization of 
RoadMABTM 
to 
inform 
individual 
dosing strategies are highlighted in 
Figure2 (above). Serum samples to 
perform drug concentration monitoring 
are collected on the same day as the 
infliximab infusion and one week after 
the first induction dose. All serum 
samples will be sent to Esoterix, 
LabCorp specialty lab (Calabasas, 
CA) with results sent to the data 
coordination center. For the pilot 
study, 
all 
drug 
concentrations, 
antibody to infliximab concentrations, 
and covariates will be entered by the 
CRC into the current version of RoadMABTM. Data accuracy will be assured by a separate study 
coordinator and the PI. Future versions of RoadMABTM are planned to extract these data directly 
from the EMR. 
 
Dose and dosing interval selection.  
Induction: For RoadMABTM to perform Bayesian estimation during induction, a minimum of the 
patient’s weight (in last 30 days), serum albumin and nCD64 will be required for the study. 
Additional covariates will be entered into the model, if pertinent (prednisone use) or are available 
(ESR). ATI cannot occur prior to the first dose and therefore will not be entered into the induction 
model.  Following data extraction (results of biomarkers) the treating physician will be alerted of 
the dosing recommendations made by RoadMABTM and the study team. The treating physician 
will then enter the infliximab starting dose into the EPIC EMR infusion plan as per policy at 
CCHMC. 
 
Maintenance:  For RoadMABTM to perform Bayesian estimation prior to the first maintenance 
dose and during maintenance, a minimum of the patient’s weight (in last 30 days), serum albumin, 
nCD64, previous infliximab dose (mg), date/time of last administration and the latest results of 
TDM will be required for this study. With frequent testing and real-world patient simulations, we 
have found therapeutic targets are more reliably achieved when all covariates (ESR, serum 
albumin, nCD64, prednisone use and presence of anti-drug antibodies) are available. 
RoadMABTM, however, utilizes only available data to formulate a dose recommendation (it does 
not impute missing data). Following data extraction (results of biomarkers) and at a minimum of 
two weeks prior to the next infliximab infusion clinicians will be alerted of the dosing 
recommendations made by RoadMABTM and the study team. The treating physician will then enter 
the infliximab dose and interval into the EPIC EMR infusion plan as per policy at CCHMC. 
 
As this is a pragmatic clinical trial and the study team can not ensure timely third-party insurance 
coverage of dosing recommendations, the treating physician will continued to be notified of the 
RoadMABTM dosing recommendation throughout the study period to improve the likelihood of 
achieving the aforementioned drug concentration targets.  
 
Importantly, based on previous safety data for infliximab,22 the RoadMAB dashboard is enhanced 
to only provide dosing recommendations that range from 5-12.5 mg/kg with rounding up to the 
nearest 100 mg (each infliximab vial is supplied as 100 mg). The center PI will oversee each 
prescribed regimen to ensure compliance with this recommendation. However, the final dose and 
interval are left to the discretion of the treating physician.  

 
 
Page 22 of 50 
REMODEL 02.14.22 
Individual and Overall Study Stopping Rules.    
 
Although infliximab is FDA-approved to be given at 0, 2, 6 weeks for induction and every 8 weeks 
during maintenance phase of therapy, clinicians frequently prescribe variable off-label doses and 
frequencies. Therefore, any patient that receives an infusion two weeks earlier than the FDA-
approved induction schedule (first 3 doses) will be considered a treatment failure and evaluated 
in an intention-to-treat analysis using a model-predicted infusion three (week6) trough 
concentration. Once a treatment failure, no further dosing strategies will be presented for that 
individual patient. During maintenance, infusions every four-eight weeks will be permitted. 
Patients requiring doses >15 mg/kg every 4 weeks will be considered a treatment failure and the 
dashboard will no longer be utilized for dosing recommendations (study participation is complete). 
These patients will be evaluated in the intention-to-treat analysis. 
 
Additionally, individual patients will be discontinued from this Dashboard study if rescue therapies 
are used in the event of loss of infliximab response. Rescue therapies include >3 infliximab 
induction infusions before week6, hospitalization for IV corticosteroids, hospitalization for severe 
infection or hospitalization for any surgery.  
 
If the participant meets the stopping criteria, we will continue to record and collect subjective 
outcome measures and biochemical specimens up until week 26 for an intention-to-treat analysis.  
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Infliximab is stored and processed for administration by the CCHMC pharmacy. All infusions will 
occur at a CCHMC facility (Burnet or Liberty campuses). 
 
Infliximab doses and frequency are entered in the electronic medical record (EMR, Epic) with an 
infusion plan (order).  Patients will not be eligible for infliximab home infusions during this study.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
The manufacturer of infliximab is: 
 
Manufacturer Information: 
Janssen Biotech, INC 
800 Ridgeview Drive 
Horsham, PA 19044 
U.S. License No 1864 
 
 
  
 
The manufacturer of infliximab-dyyb is: 
 
Manufacturer Information: 
Celltrion, INC 
23, Academy-ro 
Yeonsu-gu, Incheon, 22014, Republic of Korea 

 
 
Page 23 of 50 
REMODEL 02.14.22 
U.S. License No. 1996 
 
Distributed by: 
Pfizer Labs 
Division of Pfizer, Inc. 
New York, NY 10017 
 
The manufacturer of infliximab-abda is: 
 
Manufacturer Information: 
Samsung Bioepos Co., Ltd  
107, Cheomda-daero 
Yeonsu-gu, Incheon, 21987, Republic of Korea 
U.S. License No. 2046 
 
Distributed by: 
Merck Sharp & Dome Corp 
A subsidiary of Merck & Co., Inc. 
Whitehouse Station, NJ 08889 
 
The manufacturer of infliximab-axxq is: 
 
Manufacturer Information: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Per the manufacturers, single use vials contain 100 mg of infliximab for final reconstitution volume 
of 10 ml. Product must be refrigerated at 2ºC to 8ºC. Do not use the medication beyond the 
expiration date located on the carton and the vial. Infliximab contains no preservatives.  
 
 
6.2.4 PREPARATION 
 
The treating physician will calculate the infliximab dose and order the selected dose into an 
infliximab infusion plan within the EPIC system. The CCHMC pharmacist will then prepare 
infliximab as directed by the package insert.  
Following the preparation of the medication by the pharmacy: 
1. Pre-medications are not necessary for the study but it is typical for patients to receive 
acetaminophen (10-15 mg/kg) PO 30 minutes prior to the infliximab infusion and/or 
diphenhydramine (0.5-1 mg/kg) PO 30 minutes prior to the infusion.  
2. The infusion must be administered intravenously over a period of not less than 2 hours. 
3. Prior, during and up to 30 minutes after the infusion, the patient is monitored for any infusion 
related adverse events.  

 
 
Page 24 of 50 
REMODEL 02.14.22 
4. If at any time during or after the infusion, the subject develops fevers, chills, pruritus, urticaria, 
chest pain, shortness of breath, symptomatic hypotension or hypertension or any other 
abnormal vital signs, the infusion is immediately stopped. For subjects at the Burnet campus, 
the gastroenterology team on call is notified. For subjects at the Liberty campus, the On-call 
Hospitalist for infusion reactions is notified. Whether the infusion is restarted or discontinued 
is then at the discretion of the on-call physician.  
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
No randomization will occur with the pilot and feasibility study. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
 
We will obtain the actual infliximab dose prescribed by reviewing the electronic medical record. In 
our CRF, we will document whether the starting dose was different than ALD guidelines (5 mg/kg) 
and whether the selected dose (actually infused) differed from the dose recommended by the 
physician decision support tool, RoadMABTM.  
 
6.5 CONCOMITANT THERAPY 
 
Concomitant medications, including prescription medications, over-the-counter medications, and 
supplements will be recorded at all study visits.  The following medications are not allowed – use 
of the drugs are cause for discontinuation from the study: 
 
• 
IV antibiotics at the start of induction or during maintenance 
• 
PO antibiotics after induction (after the 3rd dose) 
• 
Immunomodulators including 6-mercaptopurine, azathioprine or methotrexate up to seven 
days before the first infusion 
• 
Other investigational agents up to one month before the first infusion 
• 
IV corticosteroids at the start of induction or during maintenance 
 
Orally administered doses of corticosteroids (prednisone, prednisolone or budesonide) are 
permitted as long as they do not exceed >1 mg/kg or >40 mg daily.   
 
6.5.1 RESCUE MEDICINE 
   
Rescue medications in the event of infliximab non-response, will not be provided by the study 
sponsor.  Participants with a treatment failure will be treated per the treating physician and will be 
discontinued from the dosing study.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
The study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Circumstances that may warrant termination or suspension include but are not 
limited to: 

 
 
Page 25 of 50 
REMODEL 02.14.22 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
If the study is prematurely terminated or temporarily suspended, the PI will promptly inform the 
CCHMC IRB, study sponsor (Crohn’s and Colitis Foundation, Cincinnati Children’s Research 
Foundation), medical monitor and provide the reason(s) for the termination or temporary 
suspension.  Resumption of the study will not take place until the concerns related to the 
termination or suspension are addressed and satisfy the Sponsor, the medical monitor and the 
IRB. 
If the study is prematurely terminated, a final visit will be scheduled for participants who are active 
in the study.  
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant non-compliance with study intervention by the subject 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded.  
Subjects who sign the informed consent or assent form and receive infliximab with/without the 
dose suggested by the Dashboard, and subsequently withdraw, or are withdrawn or discontinued 
from the study, will not be replaced. 
A total of 20 subjects with CD that meet the inclusion/exclusion criteria will be enrolled. 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for a scheduled visit 
and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The research coordinator will attempt to contact the participant and reschedule the missed 
visit and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 

 
 
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REMODEL 02.14.22 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 SAFETY AND FEASIBILITY ASSESSMENTS  
  
The following assessments and procedures will be conducted to obtain safety data: 
 
The major safety concerns for patients receiving anti-TNF biologics has been the risk of 
opportunistic infections and malignancy. As safety and feasibility are co-primary endpoints for this 
pilot trial, we will monitor all AE’s regularly and we will work with a Medical Monitor to conduct 
interim analyses to detect any adverse safety signals. Many of the safety concerns, including 
malignancy are primarily long-term considerations that are beyond the duration of most clinical 
trials.  
 
It is the responsibility of the Principal Investigator to oversee the safety of the study. The Principal 
Investigator and/or site staff is responsible for detecting, documenting and reporting events that 
meet the definition of an adverse event (AE) or serious adverse event (SAE).  
 
8.1.1 DEFINITION OF AN AE  
 
Recording of adverse events will begin at screening and monitored for during the entire study.  
 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 [a]). 
 
Moreover, an AE is any unfavorable and unintended symptom, sign, illness or experience, 
temporally associated with the use of the study drug, which develops or worsens in severity during 
the course of the study.  Inter-current illnesses or injuries should be regarded as AEs.  Abnormal 
results of diagnostic procedures are considered to be AEs if the abnormality:  
• 
Results in study withdrawal  
• 
Is associated with a SAE  
• 
Is associated with clinical signs or symptoms  
• 
Leads to additional treatment or to further diagnostic tests  
• 
Leads to a change in infliximab dosing secondary to a supra-therapeutic trough level. A 
supra-therapeutic infliximab level is defined as a concentration >40 µg/ml at infusion3 
(week 6) or any maintenance trough concentration >30 µg/ml.  
• 
Is considered by the investigator to be of clinical significance  
  
Preexisting Conditions  
A preexisting condition is one that is present and documented at the screening visit.  At baseline, 
any ongoing clinically significant abnormality should be recorded as a preexisting condition in the 

 
 
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CRF. Preexisting conditions should only be recorded as an AE if the frequency, intensity, or the 
character of the condition worsens during the study period.  
  
Anticipated (Disease Related) Events  
As CD is a relapsing and remitting condition, and participants in the trial are recruited at a time of 
disease instability requiring initiation of a new treatment regiment, it is anticipated that many 
participants will have gastrointestinal symptoms or extra-intestinal symptoms (mouth sores, 
rashes, fevers, joint pains, and/or arthritis) during the study period. These symptoms may worsen, 
fail to respond or may worsen after an initial response and could lead to hospitalization, surgery 
and/or requirement of corticosteroids. Therefore, anticipated disease-related events will not need 
to be reports separately as AE’s/SAE’s but rather reported on the CRF’s. Adverse CD-related 
Events are: 
• 
Abdominal mass 
• 
Fistula (enterocutaneous, entero-entero, perirectal, recto-vaginal, or other Crohn’s-related 
fistula) 
• 
Abscess (abdominal or perirectal) 
• 
Intestinal perforation 
• 
Intestinal obstruction 
• 
Abdominal pain 
• 
Fatigue 
• 
Abdominal tenderness 
• 
Abnormal loss of weight 
• 
Growth failure 
• 
GI bleeding related to CD 
• 
Diarrhea 
• 
Dehydration thought to be due to CD flare 
• 
Stool urgency 
• 
Nausea/vomiting thought to be due to CD or complications of CD 
• 
Arthralgia/arthritis 
• 
Uveitis/episcleritis 
• 
Ankylosing spondylitis 
• 
Cutaneous manifestations of CD (pyoderma gangrenosum, erythema nodosum) 
• 
Abdominal surgery or complications of abdominal surgery due to CD 
• 
Anemia thought to be due to CD 
 
Abnormal Laboratory Values  
A clinical laboratory abnormality should be documented as an AE if any one of the following 
conditions are met:   
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• 
The abnormality suggests a disease and/or organ toxicity  
• 
The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc.  
  
8.1.2 DEFINITION OF A SERIOUS AE  
 
AEs are classified as serious or non-serious.  A serious AE is any AE that is:   

 
 
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REMODEL 02.14.22 
• 
Fatal 
• 
Life-threatening  
• 
Requires or prolongs a hospital stay  
• 
Results in persistent or significant disability or incapacity  
• 
A congenital anomaly or birth defect (in the offspring of a study participant)  
• 
An important medical event  
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.   
  
Hospitalization, Prolonged Hospitalization or Surgery  
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as a SAE unless specifically instructed otherwise below. Any condition responsible for 
surgery should be documented as an AE if the condition meets the criteria for an AE.   
  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
AE in the following circumstances:  
 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an AE if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful.  
  
• 
As discussed above in the Anticipated AE section, data regarding failure to respond and/or 
worsening of CD are collected as part of study outcomes and are captured in the CRFs. 
These anticipated disease-related events will not need to be reported separately as 
AEs/SAE’s. However, if the PI believes the frequency or severity of a Crohn’s exacerbation 
or complication deem it to be a SAE, then this can be reported at the discretion of the PI.   
All AEs that do not meet any of the criteria for serious should be regarded as non-serious 
AEs.   
  
8.2 PREGNANCY  
Any pregnancy that occurs during the study and up to 16 weeks following the last study dose 
must be reported on a clinical trial pregnancy report form within 2 weeks of learning of the event 
(self-report) and recorded as an AE. This will include any pregnancy in a female trial participant. 
The pregnancy must be followed in order to confirm the outcome and health status of the mother 
and child.  
  
Maternal and fetal pregnancy complications and elective terminations for medical reasons must 
be reported as an AE or SAE per the definitions above and the instructions in the following section. 
Spontaneous miscarriage must be reported as a SAE.  
  
8.3 RECORDING OF AE’S AND SAE’S  
On enrollment in the study, subjects will be instructed to contact the investigator if a SAE occurs, 
so that appropriate measures can be taken.  At each contact with the subject, the investigator 
must seek information on AEs by specific questioning and, as appropriate, by examination.  
  

 
 
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All AEs occurring from the date of the first dose of infliximab (or biosimilar) and for 7 days following 
the final dose of study medication, must be recorded.  Any SAE that occurs within 14 days 
following the final dose of study medication should be recorded and reported according to IRB 
guidelines. 
 
Information on all AEs will be recorded in the source document, and also in the appropriate AE 
module of the CRF.  All clearly related signs, symptoms, and abnormal diagnostic procedures 
results should be recorded in the source document. 
  
All unresolved AEs should be followed by the investigator until the events are resolved, the subject 
is lost to follow-up, or the AE is otherwise explained.  At the last scheduled visit, the investigator 
should instruct each subject to report any subsequent event(s) per the reporting timelines noted 
above.   
  
8.3.1 RECORDING AND EVALUATION OF AES  
The following will be documented for each AE: 
• 
Nature of the event  
• 
Start date and stop date  
• 
Severity  
• 
Relationship to study treatment (causality)  
• 
Action taken  
• 
Outcome  
• 
Expectedness  
• 
Seriousness (per SAE definition)  
  
Severity  
The severity is evaluated by the investigator as follows:  
Mild - event/symptom does not interfere with normal daily activities (Grade 1)  
Moderate - event/symptom interferes with normal daily activities (Grade 2)  
Severe - event/symptom prevents normal daily activities (Grade 3 or 4)  
  
Relationship to Study Treatment  
The relationship is evaluated by the investigator as follows:  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals.  
 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely 
to be attributed to concurrent disease or other drugs or chemicals. 
 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 

 
 
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REMODEL 02.14.22 
soon after discovery, it can be flagged as requiring more information and later be upgraded 
to “probably related” or “definitely related”, as appropriate. 
 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
 
• 
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
 
Expectedness  
An AE is considered “unexpected” if the particular event/symptom is not listed as a common 
adverse reaction in the package insert of the of the study drug. An AE is also considered 
“unexpected” if the particular event/symptom occurs at a greater severity and/or specificity than 
listed in the package insert.   
  
For the purpose of this trial, all expected AEs will be indicated on the AE CRF. The determination 
of the expectedness for SAEs will be made by the medical monitor based upon the appropriate 
package insert for infliximab.  
  
The following will be considered expected AEs:  
The most common adverse reactions caused by infliximab include:  
• 
Infections (e.g. upper respiratory, sinusitis, and pharyngitis)  
• 
Infusion-related reactions  
• 
Headache Elevation of liver enzymes 
  
In addition to the items documented for each AE (see section 8.3.1), the following will be 
documented for each SAE:    
• 
Brief description of the event  
• 
Category of the event   
o Death,   
o Life-threatening 
o Hospitalization 
o Disability / incapacity 
o Congenital anomaly / birth defect 
o Intervention required to prevent permanent impairment 
o Other (per the investigator’s discretion) 
• 
Intervention taken 
• 
List of relevant tests, laboratory data, history, including pre-existing medical conditions  
 
 
 
 
 
 

 
 
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8.4 MANAGEMENT OF AES  
 
8.4.1 GENERAL  
The clinical course of each event should be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  Serious AEs that are 
still ongoing at the end of the study period must be followed up to determine the final outcome.    
 
8.4.2 MANAGEMENT OF ABNORMAL LABORATORY RESULTS  
All laboratory values outside of the normal range will be repeated if judged appropriate by the 
Primary Investigator and/or Medical Monitor to ensure the validity of the abnormal result. The 
investigator will document all laboratory values on the relevant page of the CRF and will assess 
the etiology of the clinically relevant abnormal laboratory values.  
  
Monitoring of abnormal liver enzymes - If the AST or ALT (LFT’s) increase ≥2 times the upper 
limit of normal (2x ULN) after the start of the study medication, the investigator will repeat the 
measurement of LFT’s after 2-3 weeks. If LFTs normalize, the patient will continue with current 
dose of infliximab, however, if LFTs remain 2x ULN at the second laboratory draw, the dose of 
infliximab should be reduced to 5 mg/kg (rounded to nearest 100 mg)  if the participant was 
receiving a dose of >7.5 mg/kg. If the participant was receiving a dose of infliximab <7.5 mg/kg, 
then another check of LFT’s should be performed within 4 weeks. If the LFT’s normalizes or return 
to less than 2X ULN, then patient should remain on the current dose and further laboratory 
monitoring of the LFT’s should be performed in the setting of the routine laboratory draws in the 
context of each infusion.  If LFTs remain 2x ULN upon recheck, the participant must undergo 
further investigations which may require additional laboratory testing (infectious causes of 
hepatitis, investigations for autoimmune causes of hepatitis and/or other metabolic disorders of 
the liver).  
  
8.4.3 PREGNANCY  
All female subjects will have a urine pregnancy done before starting infliximab as pregnancy is an 
exclusion for this study. Any confirmed pregnancy during the study will result in an urgent clinic 
visit to the primary treating physician to discuss safety of infliximab during pregnancy. Infliximab 
has been shown to be safe during the first and second trimesters of pregnancy,35 with a discussion 
with the clinician for continued use during the final trimester. Therefore, the patient will be removed 
from the study but whether they will continue on infliximab will be discussed with the participant’s 
primary physician, the PI and the Medical Monitor.  
 
All pregnancies will be followed in order to confirm the outcome and health status of the mother 
and baby.  
 
8.5 REPORTING OF SERIOUS AES  
 
In addition to recording all AEs and SAEs in the CRF, the PI must conform to the AE reporting 
timelines, formats and requirements of the IRB (institutional review board), and any other 

 
 
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REMODEL 02.14.22 
regulatory entity to which they are responsible. At a minimum those events that must be reported 
are those that are: 
• 
Related to study participation 
• 
Unexpected 
• 
Serious or involve risks to subjects or others 
• 
Not deemed to be a consequence of the patient’s underlying CD  
  
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes:  
• 
Study identifier  
• 
Subject number  
• 
A description of the event  
• 
Date of onset  
• 
Current status  
• 
Whether study treatment was discontinued  
• 
The reason why the event is classified as serious  
• 
Investigator assessment of the association between the event and study treatment  
  
Any SAE (including death, irrespective of the cause) occurring during or for up to 14 days after 
the end of the study must be reported without delay, i.e. within 24 hours. The Serious AE (SAE) 
form must be completed by the PI, and sent by facsimile to the study Safety Medical Monitor:  
  
Within the following 48 hours, the PI must provide further information on the SAE or the 
unanticipated problem in the form of a written narrative. This should include a copy of the 
completed SAE form, and any other diagnostic information that will assist the understanding of 
the event, including de-identified medical and/or hospital records, where applicable.  Significant 
new information on ongoing SAEs should be provided promptly to the study sponsor. The 
investigator will keep a copy of this SAE form on file at the study site.  
  
The Safety Medical Monitor will perform a regular assessment of the number and type of SAEs.  
 
8.5.1 INVESTIGATOR REPORTING  
The PI is responsible for safety reporting to the central IRB within 10 working days.  Copies of 
each report and documentation of IRB notification and receipt will be kept in the investigator’s 
study file.   
 
8.6 FEASIBILITY EVALUATION 
 
8.6.1 THIRD PARTY COVERAGE 
As noted, infliximab dosing is labeled as 5 mg/kg to be given at 0, 2, 6 and then 5 mg/kg every 8 
weeks. Prior to the start of infliximab, prior authorization is required by the third party payer for all 
participants. As children with more severe Crohn’s disease frequently require doses up to 15 
mg/kg to achieve intestinal healing, RoadMABTM will calculate a starting dose and present this 
dose to the treating physician. If the recommended starting dose is not covered by third party 
payer, every effort will be made to contact the payer for justification of off-label dosing. If the dose 
is still denied, the physician can then petition the payer a second time before the second or 

 
 
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REMODEL 02.14.22 
subsequent maintenance doses. All outcomes related to insurance coverage are important 
treatment outcome measures that may result in changes in the study design for the subsequent 
research trials.   
 
Additionally, studies have suggested that infliximab infusions <8 weeks may be more effective at 
achieve target concentrations and improved outcomes during maintenance. Therefore, the co-
primary endpoint includes a feasibility outcome measure. Specifically, we will track the following 
within our CRF forms: 
• 
Rate of Insurance approval for doses >7 mg/kg during induction 
• 
Rate of Insurance approval for doses >7 mg/kg and/or frequency <8 weeks during 
maintenance 
 
8.6.2 PHYSICIAN RESPONSE TO DOSING RECOMMENDATIONS 
This is a pragmatic clinical trial. All starting and subsequent dosing regimens will be presented to 
the treating physician utilizing the RoadMABTM Dashboard. However, the final dose and dosing 
interval (weeks) will remain at the discretion of the physician. If the treating physician does not 
follow the prescribed dose at the first infusion, the subject will continue in the study and 
subsequent dose recommendations will continue as described in Figure2 and presented to the 
treating physician. In the CRF, we will record prior to each dose: 
• 
Rate of physician adherence to the dashboard dosing recommendation 
• 
Reason(s) the recommendation was not followed 
 
8.6.3 SUBJECT ADHERENCE TO LABORATORY COLLECTIONS 
It is routine at CCHMC that all patients receiving infliximab infusions undergo laboratory 
assessments prior to starting infliximab and prior to each subsequent infusion. The following is a 
list of REQUIRED pre-infliximab laboratory and with each subsequent infliximab infusion 
assessments for inclusion in this study 
1. CBC with differential 
2. Albumin, AST, ALT 
3. Neutrophil CD64 activity ratio (nCD64) 
 
The following laboratory tests will be RECOMMENDED pre-infliximab and with each subsequent 
infliximab infusion: 
1. Erythrocyte sedimentation rate (ESR) 
2. GGT 
 
The following laboratory tests will be required to receive subsequent (after infusion3) dashboard 
recommendations: 
1. Infliximab concentration 
2. Antibody to infliximab concentration 
 
In this study, we will be collecting additional blood specimens prior to each infliximab infusion, 5-
10 days after the first infusion (lab-only visit) and a blood collection 30-60 minutes following 
specific infliximab infusions (infusion1, infusion2, infusion3, infusion4, and infusion6). We will track 
subject’s adherence to: 
• 
Blood specimen collection prior to each infliximab infusion 
• 
Blood specimen collection 5-10 days following the first infliximab infusion 

 
 
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REMODEL 02.14.22 
• 
Rate of blood specimen collection 30-60 minutes following pre-specified infusions.  
 
 
8.7 EFFICACY ASSESSMENTS  
  
Table2 in Section 3.0 is an overview of the efficacy endpoints that we are exploring during this 
study. The primary efficacy outcomes are infliximab trough concentrations at week6 and during 
maintenance, clinical response, clinical remission, fecal calprotectin response, fecal calprotectin 
remission, and transmural healing (as defined by MRI of the abdomen).  
 
The following assessments and procedures will be conducted to obtain efficacy endpoint data: 
 
Blood Collection: Participant will have up to 20 ml of blood obtained prior to each infusion, 5-10 
days after starting infliximab (V2), and up to 6 ml of blood obtained 30-60 minutes after infusion1, 
2, 3, 4, 6. Aliquots of blood will be utilized by the Minar laboratory for biomarker discovery testing, 
the Cancer and Blood Diseases Institute Clinical Laboratories at CCHMC for neutrophil CD64 
activity ratio and Esoterix (LabCorp specialty lab, Calabasas, CA) for infliximab concentration and 
antibody to infliximab concentration testing. The remaining blood will be centrifuged and the 
plasma placed in -80C for future biomarker testing.  
 
Stool Sample Collection: Participants will collect stool samples at home the day before, or on 
the day of the infus1 (V1), infus3 (V4), infus4 (V5) and at study end Infus6 (V7). Participants will 
be asked to mail their stool sample with the provided stool collection materials to the CCHMC 
Minar Laboratory. If the participant brings to clinic or the infusion visit, the study coordinator will 
transport that sample to the Minar Laboratory for storage at -80C until batched for fecal 
calprotectin and lactoferrin testing can be completed. Additional stool will be stored for 
metagenomics and/or 16S sequencing and analysis. Shipping supplies, instructions, and mailing 
labels will be provided. Parents and subjects will be reminded (email or by phone) of the stool 
collections. All collection and shipping instructions including the shipping materials will be 
provided to the subject.  
Fecal biomarkers: Fecal calprotectin will be measured using an ELISA kit with an inter-assay 
precision CV 6.6-14.5% (Buhlmann, Switzerland)36 and fecal lactoferrin measured with ELISA 
(CV 7.9-16%, IBD-SCAN® TechLab, Blacksburg, VA). 
16S Sequencing and Analysis:  DNA will be subjected to 16S rRNA amplicon sequencing (V4 
region, 2x175bp). Operational taxonomic unit (OTU) clustering and taxonomic assignment will 
be performed with the 16S bioBakery workflow built with AnADAMA2, which incorporates ea-utils 
and the UPARSE pipeline (version 8.1).  Microbial taxonomy is based on the Greengenes 16S 
rDNA database (version 13.5). Samples will be subsequently filtered based on number of 
assigned reads (min 3,000 reads).  Shotgun metagenomics sequencing with an average of 
10,000,000 paired-end reads per sample (150nt per read), will be employed. Relative pathway 
abundance of each sample will be quantified by HUMaN v2.0.37  
 
Demographics: Information related to participant age and gender will be collected as part of the 
review of medical records conducted for screening (see below). Race will be collected at Visit 1. 
 
Plasma collection:  Plasma will be obtained for neutrophil CD64 surface expression, soluble 
CD64, and future proteomic discovery testing.  In addition to the nCD64 conducted by the CCHMC 
CLIA-certified Immunology Laboratory, the Minar Laboratory will determine a research Neutrophil 
CD64 Activity Ratio (NCAR): the expression of CD64 on neutrophils is analyzed by labeling 

 
 
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REMODEL 02.14.22 
peripheral blood with CD64, CD163 (a monocyte marker), and CD45 (a pan-leukocyte marker) 
and analyzing the cells by flow cytometry (FACSCantos, BD Biosciences). The CD64 expression 
on neutrophils is reported as an activity ratio comparing the neutrophil CD64 mean fluorescence 
intensity (MFI) to the negative internal control (lymphocyte CD64 MFI). Soluble CD64: Human 
FCGRI/CD64 ELISA will be performed according to the manufacturer’s manual (LifeSpan 
BioSciences, Seattle, WA). Additional laboratory testing: Routine labs at each infusion includes a 
complete blood count, CRP, ESR, serum albumin, ALT and AST. As ESR, albumin and CRP are 
vital to our analyses, if these are not ordered by the treating physician, the blood collected prior 
to each infusion will be sent to the CCHMC CLIA-approved laboratory for testing.  
 
MRI abdomen: Obtaining serial abdominal scans is also another method to evaluate response to 
treatment as transmural healing (defined by abdominal imaging) has been associated with 
improved patient outcomes.38 Therefore, we will provide the option to each participant to obtain 
an approximately 30 minute MR scan (using oral contrast, Breeza®, or other comparable product, 
or water) for all study participants. If the participant has previously had a MR scan for clinical 
purposes, we will use the results and images for this research study. We will utilize a validated 
radiographic severity scoring tool (MARIAs).39 The MARIAs will be calculated by one central 
reader at CCHMC (Dr. Jonathan Dillman, an experienced radiologist who has published on MR 
use in pediatric CD40). The MARIAs is based on presence/absence of intestinal wall thickening, 
mural edema, fat stranding and ulcerations in each segment of the colon and distal ileum with 
total scores ranging from 0-30.39 Although the diagnostic accuracy of the MARIAs has not been 
evaluated in children with CD, we expect the tool to perform equally well in this population as the 
MARIAs was shown to have excellent correlation with endoscopy based assessments in adult-
onset CD.39 A strong advantage 
of the MARIAs is that all 
components of the scoring can 
be 
evaluated 
with 
imaging 
sequences that do not require the 
use of paramagnetic contrast 
(such 
as 
gadolinium-based 
contrast agents). 
 
All MRIs will be reviewed by Dr. Dillman for any abnormalities.  In the case that the research MRI 
shows new findings that may result in harm to the patient (i.e., an abscess), these abnormal 
findings will be reported to both the participant and treating physician.  Otherwise, results of the 
research MRI will not be released to participants or their treating physician. 
 
8.8 ADDITIONAL ASSESSMENTS 
 
Prior to enrollment the following will be performed for screening purposes.   
 
Review of Medical Records: Existing information about potential participants will be reviewed to 
determine: 
• 
Age 
• 
Gender 
• 
Diagnosis 
• 
Current medications 
• 
Medication history 
• 
Co-morbidities 
• 
Allergies 

 
 
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REMODEL 02.14.22 
 
A HIPAA Waiver will be requested from the IRB to allow for review of records preparatory to 
research. 
 
The following assessments and procedures will be performed to determine eligibility for study 
participation and throughout the study to obtain safety data: 
 
Physical Exam and Vital Signs: The physical exam conducted by the primary gastroenterologist 
at the last clinic visit will be recorded for this study. Infus6 (V7) will also include a physical exam 
conducted by the PI. If the participant is seen (or a visit scheduled) by the treating physician within 
four weeks of the study end date, the documented exam that occurred will replace the need for 
PI examination (study-only visit). Vital signs will be collected and will include temperature, heart 
rate, respiratory rate, and blood pressure. Weight and height will also be collected at these visits. 
 
Urine Collection: Female participants who are capable of becoming pregnant will have a urine 
pregnancy test at the baseline visit. 
 
Weighted Pediatric Crohn’s Disease Activity Index (wPCDAI):  We will utilize the wPCDAI to 
measure clinical disease activity.  The wPCDAI has been validated in the pediatric CD population 
with well-established cut-points for clinical remission and relapse (Appendix).41 The wPCDAI will 
be obtained prior to each infusion and at month 6 (end of study). To be study eligible, a wPCDAI 
a value >12.5 will be required prior (up to 6 weeks prior) to infusion 1.  
 
Patient-reported Outcomes: Patient reported outcomes (PRO’s) are direct responses from 
patients (or parent proxy) and convey important aspects of health status. PRO’s can evaluate 
symptoms, signs, functional status and are a reflection of what is most important to patients about 
a condition or treatment. Additionally, PRO’s are becoming increasing important endpoints for 
clinical trials and comparative effectiveness studies. To guide the design of a future RCT, we will 
also collect patient-reported outcomes of abdominal pain and stool frequency for all patients prior 
to each infusion and infus6 (V7, See Appendix A).  
 
IBD Disability Assessment: We will assess for CD disability and quality of life using the IBD 
Disk tool while eliminating the sexual function question. This tool will be exploratory and therefore, 
optional to complete at enrollment and study completion. This will be collected from patients ≥12 
years old and completed by the parent or subject. 
 
Endoscopic Severity Score: To guide a future RCT trial which may require endoscopic 
assessments, the Simple Endoscopic Score-Crohn’s Disease (SES-CD) and Physician Global 
Assessment-Colonoscopy Score (PGA-CS) will be tabulated in participants who undergone a 
clinically indicated colonoscopy within six months prior to enrollment by reviewing the previously 
recorded colonoscopy procedure (if available) that was securely saved on VaultStream. We will 
also record SES-CD and PGA-CS for any patients who undergo a clinically-indicated colonoscopy 
during this clinical study (Appendix B). 
 
Fecal biomarkers: We will measure fecal calprotectin and/or fecal lactoferrin to assess mucosal 
inflammation. To be study eligible, the subject must have evidence of active inflammation by 
endoscopy (performed within the last 90 days) or a fecal calprotectin >250 µg/g/fecal lactoferrin 
>10 µg/g. If the subject is study eligible but has not had recent fecal calprotectin/lactoferrin 
obtained, we will ask the treating physician to order the respective fecal testing and processed in 
the CCHMC Clinical Laboratory. All costs/fees of the test will be paid by the study.  
   

 
 
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8.9 UNANTICIPATED PROBLEMS 
 
8.9.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
 
• 
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
 
8.9.2  UNANTICIPATED PROBLEM REPORTING  
 
Unanticipated problems (UPs) will be reported to the sponsor, reviewing Institutional Review 
Board (IRB), PI and to the Medical Monitor. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported in an expedited manner as 
outlined in Section 8.3.6 – SAE Reporting. 
• 
Any other UP will be reported at the time of regularly scheduled reporting 
 
 
 
8.9.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
The occurrence of any unanticipated problem that changes the safety profile of the study shall be 
incorporated into a revised version of the informed consent document(s).  The IRB will make a 
determination as to whether enrolled participants should be re-consented. 
 
 

 
 
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9 
STATISTICAL CONSIDERATIONS   
 
9.1 STATISTICAL HYPOTHESES 
 
We hypothesize that model-informed infliximab dosing that accounts for individual drug 
clearance with routine blood biomarkers to inform the starting infliximab dose will be safe, feasible 
and more accurately achieve the targeted drug exposure during induction than as-labeled 
(routine) dosing.  
 
Aim 1:  Determine the safety and feasibility of utilizing a physician support tool 
(RoadMABTM dashboard) to dose infliximab during induction and early maintenance.   
 
Primary Endpoint 
B. 
Rate of AE and/or SAE’s during the study 
C. 
Rate of physician, subject and third party payer (insurance) adherence to  
Dashboard dosing recommendations 
 
Aim 2: Test the performance of a physician support tool to achieve infliximab 
concentration targets. 
 
Endpoint(s):  
A. Rate of achieving infus3 (V4) infliximab concentration  between 18-24 µg/ml33 as a 
dichotomous outcome.  
B. Median difference of infus3 (V4) levels between cases and controls (historic controls that 
were previously enrolled and received ALD infliximab during induction). 
C. Rate of achieving infus2 (V3) level between target range of 26-34 µg/ml as a dichotomous 
outcome. 
D. Median difference of infus2 (V3) levels between cases and controls. 
E. Rates of achieving maintenance targets infus4-6 (V5-7) between 5-10 µg/ml. 
F. Rate of development of anti-infliximab antibodies at any infusion between cases and 
controls. 
G. The proportion of patients in clinical response and remission at infus4 (V5) and infus6 
(V7). 
a. Clinical response: improvement in baseline wPCDAI by >17.5 or a wPCDAI<12.5 
b. Clinical remission: wPCDAI <12.5 and off corticosteroids 
H. Rate of sustained remission: wPCDAI <12.5 and off prednisone for all visits from infus4 
(V5) to infus6 (V7). 
I. The proportion of patients in fecal calprotectin response and remission at infus4 (V5) and 
infus6 (V7) 
a. Fecal calprotectin response: ≥50% improvement in fecal calprotectin. 
b. Fecal calprotectin remission: fecal calprotectin <250 µg/g. 
J. Rate of transmural ileal, colonic and total bowel healing at infus6 (V7) by MRI. 
a. Ileal healing: ileum subscore stage 0 (score = 0)  
b. Colonic healing: all segments of colon subscore stage 0 (score = 0).  
c. Total bowel healing: total ileum and colonic subscore is not greater than stage 0 
on either individual score. 
 
 
 

 
 
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9.2 SAMPLE SIZE DETERMINATION 
The rational to enroll 20 participants for the test cohort is to evaluate the safety of the intervention 
along with the feasibility of adherence to the dosing recommendations.  
In terms of our efficacy endpoints, we understand that this pilot study will be primarily descriptive. 
However, we have gathered data from a previously enrolled, observational cohort of 25 CD 
patients who received both ALD (5 mg/kg) and ALD induction intervals (at 0, 2 and 6 weeks). 
These 25 previously enrolled subjects are considered the control cohort for this study. We found 
40% of the 25 subjects achieved the infusion3 target (18-24 µg/ml). We estimate a sample size 
of 20 subjects will have 51.9% power with the assumption the dashboard will achieve the infusion3 
target in 70% of those enrolled (14 subjects). With this vital pilot data, we will be able to more 
effectively design our larger, confirmatory study.  
Consideration of relevant biologic variables. Biologic variables which may influence infliximab 
concentrations include age, gender, race/ethnicity, weight, serum albumin, and extent and 
severity of mucosal inflammation. Of these, extent of Crohn’s colitis and serum albumin are likely 
to have the greatest effect.17, 44 We will evaluate these difference in our statistical analysis, 
however, serum albumin is already accounted for as it is a covariate in our model-based dosing 
scheme. If a significant effect of extent of colitis is found, we will utilize this data for our future 
RCT. We anticipate enrolling equal numbers of males and females between ages 6 and 22 years 
old and Caucasian (90%) and African-American (10%) subjects in proportion to the overall 
CCHMC CD population.  We will exclude younger children (<6 years of age) pending identification 
of any un-anticipated safety signals.  
Potential Problems and Alternative Approaches.  With model-based dosing, the first dose will 
be based on patient’s weight, albumin, and nCD64 using population PK and Bayesian estimation. 
As this is a pragmatic study, there is the potential that the prescribed dose will be denied by the 
third party payer. In this case, the treating physician will have the opportunity to appeal that 
decision. If the recommended dose is still not covered despite the appeal, another attempt will be 
made by the treating physician at a subsequent infusion. This will be valuable data when 
designing the confirmatory study as the alternative would be for the Study team to provide the 
additional infliximab vials needed to comply with the dashboard recommended dose.  
 
9.3 POPULATIONS FOR ANALYSES 
 
Our primary analysis will be on a per protocol basis, including only patients who were prescribed 
infusion1 as suggested by the decision support tool.  Our secondary analysis will be based on an 
Intent to Treat (ITT) schema, with each enrolled patient included in the final analysis.  
 
9.4 STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Descriptive statistics and graphical analyses will be used to describe rates of AE’s, SAE’s and 
feasibility assessments. In addition, rates of achieving targeted infliximab concentrations, along 
with rates of biochemical and clinical remission will be determined. The control group includes the 
25 patients that received ALD infliximab during induction. The test cohort includes all patients 
enrolled in this Pilot trial.   
 

 
 
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9.4.2 ANALYSIS OF PRIMARY AIM ENDPOINTS 
 
Primary outcome: As a pilot and feasibility study, all primary outcomes (safety and feasibility) 
will be reported using descriptive statistics. Rates of AE’s and SAE’s will be compared to those 
reported in previous infliximab clinical studies and the control cohort.  
 
In the infliximab clinical trial conducted in children with CD2, 94.2% of all patients who received 
infliximab after week 10 (103 patients) had an adverse event with 5.8% of patients stopping 
infliximab because of the adverse event. Serious adverse events were found in 14.6% with 6.8% 
having a serious infection. Additional safety concerns during the first 6 months of therapy include 
infusion reactions (17.5%), transient elevations in liver enzymes (6%) and serum sickness-like 
reactions (0%).2 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary outcomes:  
1. Percent of patients achieving infliximab goal concentrations (18-24 µg/ml) at infusion3 will 
be compared between the Pilot (n=20) and observation cohort (n=25). Statistical 
differences will be assessed by the Fisher’s exact test. Differences in IFX dosing and IFX 
clearance will be evaluated between patients who did and did not achieve infusion3 goal 
concentrations. 
  
2. In addition, we will compare additional outcome measures between the pilot and 
observation 
cohort. 
These 
outcomes 
include 
infliximab 
concentrations, 
biochemical/clinical remission and rate of antibody to infliximab formation. Time to clinical 
remission, biochemical remission and antibodies to infliximab will be compared between 
the two cohorts utilizing the log rank test and Kaplan-Meier survival curves. MRI scores 
will be assessed for the Pilot cohort only with rates of transmural healing investigated 
between those with therapeutic infliximab exposure compared to those who failed to 
achieve the targeted infliximab concentrations. 
 
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
 
Descriptive statistics and graphical analyses will be used to describe clinical and demographic 
characteristics, baseline fecal calprotectin/lactoferrin, baseline wPCDAI and QOL. 
 
9.4.5 PLANNED INTERIM ANALYSES  
 
We will evaluate the safety of model-informed dosing after the first 10 patients complete induction 
(infusions at week 0, 2 and 6).  
 
Safety.  If three or more subjects report a serious adverse event during induction, we will 
determine with the Medical Monitor whether model-informed dosing is safe. We do not expect any 
increase safety risk as off-label infliximab dosing is commonly used45 
 
As supra and sub-therapeutic levels can be associated with adverse treatment outcomes, we will 
also evaluate the accuracy of the model after the first 10 patients with specific attention to 
infusion3 (week6, 18-24 µg/ml) and infusion4 (week14, 5-10 µg/ml) concentrations. Importantly, 
the accuracy may be confounded by the apriori infliximab concentration targets for individual 

 
 
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patients and their individual dosing interval (during the maintenance phase). Therefore, both 
confounders will be considered during this interim analysis.  
We expect that ≥6/10 patients will achieve these aforementioned targets. If these 
targets are not being met, we will determine with the Medical Monitor whether model-
informed dosing is efficacious. If the minimum concentration is not achieved during 
maintenance (>5 µg/ml) for >1 infusion, a pharmacokinetic consult with Alexander 
Vinks, PharmD, PhD and the PI will be arranged to provide dosing guidance for 
subsequent infusions. Likewise, if the infliximab level exceeds 2x the upper range 
during maintenance (>20 µg/ml) for >1 infusion, a pharmacokinetic consult will be 
arranged to provide dosing guidance for subsequent maintenance infusions during the 
study period. 
 
9.4.6 SUB-GROUP ANALYSES 
 
Our primary Aim 1 analysis will be on a per protocol basis, including only patients who received 
model-informed dosing at infusion1.  Our secondary analysis will be based on an Intent-to-Treat 
(ITT) schema, with each patient included in the analysis regardless of whether the patient decision 
tool was utilized for dosing.    
 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be tabulated in an unlimited fashion. 
 
9.4.8 EXPLORATORY ANALYSES 
We will test for effects of age, gender, race, infusion3 fecal biomarkers, and additional blood 
biomarkers (such as pre-treatment plasma proteins and pre-maintenance plasma proteins) in an 
exploratory manner to guide design of the larger, multi-center clinical trial 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Consenting document(s) will be used to obtain informed consent and parental permission and 
assent, when required, from participants, along with a consent process note.  CCHMC will provide 
an English consenting template(s) to be used that contain all required elements of consent 
including details about the study intervention, study procedures, and risks. All consent forms (and 
any subsequent updates) will be IRB approved prior to use in the study.  Delegation for site staff 
to perform consenting procedures will be documented on the Delegation of Authority Log and will 
be signed by the PI. 
 
 
 
 

 
 
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10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the documents. The investigator or a designated study member will explain the research study to 
the participant and answer any questions that may arise. A verbal explanation will be provided in 
terms suited to the participant’s comprehension of the purposes, procedures, and potential risks 
of the study and of their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form(s) and ask questions prior to signing. The participants 
should have the opportunity to discuss the study with their family or surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document(s) prior 
to any procedures being done specifically for the study.  If a participant turns 18 years of age (or 
as defined by state law for legal age of consenting) while participating in the study, re-consent will 
be obtained from the participant.  Once all data is collected and follow up is complete, re-consent 
will not be requested for analysis of the existing data. 
 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document(s) will be given to 
the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the 
participant undergoes any study-specific procedures. The rights and welfare of the participants 
will be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
 
Consent may take place by several methods: in-person paper consent, in-person electronic 
consent (using REDCap for the eConsent) or over the telephone (via paper or REDCap for remote 
eConsent) or video chat*. If consent takes place remotely via phone call and/or remote econsent, 
subjects may email, mail, text, fax, or use the eConsent platform to provide staff with the signed 
document.  A self-addressed stamped envelope will be provided to the participant for them to 
return the consent through regular mail. 
 
* When using a video chat method use tools such as FaceTime, Skype, and/or other institutionally 
approved methods; and, use a common-sense approach to privacy (e.g., away from your own 
family, delete call logs, etc.) 
 
Signatures of the subject may not always occur on the same date as the consent discussion 
depending on how and when the subject returns the signed consent. The staff member who 
conducted the consent discussion will document this in a detailed informed consent process note, 
but not necessarily on the consent document itself. No matter the consenting process, study 
procedures will not occur prior to a fully executed consent form.  Consent will be obtained following 
institutional SOPs. REDCap eConsent will not replace the consenting method, it will be used as 
an additional resource for signing the consent form. A copy of the consent form will either be given 
to the subject in paper form or emailed to them via REDCap depending on how the consent is 
completed. In all cases, the consent process will be documented on the informed consent process 
note and a copy of the signed consent(s) will be kept in the patient’s medical record. 
 
Staff will make sure that the eConsent database is updated as soon as possible after a new 
version of the paper consent is approved. Staff will also make sure paper consents are used to 
consent eligible subjects in the event that the eConsent database is not updated prior to eligible 

 
 
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subjects being available for consent approach by a member of the study staff. For the reasons 
described, the eConsent will not be submitted to the IRB for approval. 
 
 
10.1.1.3 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. If the study is prematurely terminated or suspended, written notification will be 
provided to the IRB, Medical Monitor, and the funding agency.  The Principal Investigator (PI) will 
promptly inform study participants, and will provide the reason(s) for the termination or suspension 
and will be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor and IRB. 
 
10.1.2 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor. This confidentiality is extended to cover testing of biological samples in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), or regulatory agencies may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site 
will permit access to such records. 
 
The study participant’s contact information will be securely stored at CCHMC for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at CCHMC. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by CCHMC research staff will be secured and password 

 
 
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protected. At the end of the study, all study databases will be de-identified and archived at 
CCHMC. 
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at CCHMC.  After the study is completed, 
the de-identified, archived data will be stored at CCHMC for use by other researchers including 
those outside of the study.  
 
With the participant’s approval and as approved by the CCHMC Institutional Review Board (IRB), 
de-identified biological samples will be stored in the Minar Laboratory. These samples could be 
used to research the causes of Crohn’s disease, its complications and other conditions for which 
individuals with Crohn’s disease are at increased risk, and to improve treatment. The Minar 
laboratory personnel will also be provided with a code-link that will allow linking the biological 
specimens with the phenotypic data from each participant, maintaining the blinding of the identity 
of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
 
Sponsor/Principal Investigator 
- CCHMC 
Phillip Minar, MD, MS 
Associate Professor – Faculty, 
Gastroenterology, Hepatology & 
Nutrition 
Cincinnati Children’s Hospital 
Medical Center  
3333 Burnet Avenue MLC 2010, 
Cincinnati OH 45229 
513-636-7575 
Phillip.minar@cchmc.org 

 
 
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REMODEL 02.14.22 
 
Medical Monitor 
Joel R. Rosh, MD 
 
Atlantic Health System 
55 Madison Avenue 
Morristown, NJ 07960 
973-971-5676 
Joel.rosh@atlantichealth.org 
 
Dr. Minar will serve as the PI for this project. Dr. Minar will be responsible for oversight of the 
clinical trial and supervise the organization, implementation, monitoring and reporting of the 
clinical protocol. Dr. Minar will act as the primary medical contact for the clinical trial working 
closely with the CCHMC project manager to answer protocol questions and ensure appropriate 
interpretation of the inclusion/exclusion criteria as well as conformity to the treatment paradigm. 
Dr. Minar will review recruitment on a weekly basis and be in frequent communication with the 
project manager.  
 
 
10.1.5 SAFETY OVERSIGHT 
 
As off-label infliximab dosing is routinely utilized in Crohn’s disease management, no formal Data 
and Safety Monitoring Board (DSMB) will be organized.  
 
An independent Medical Monitor will be involved during the conduct of the trial for additional 
review of adverse and serious adverse events on a quarterly basis.  Review will include the 
assignment of severity, expectedness, and relatedness. 
 
10.1.6 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonization Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s).  
 

 
 
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REMODEL 02.14.22 
• 
Monitoring for this study will be performed by Office for Clinical and Translational 
Research, located at Cincinnati Children’s Hospital Medical Center. 
 
• 
Per FDA guidance “Guidance for Industry: Oversight of Clinical Investigations - A Risk-
Based Approach to Monitoring, August 2013”, a risk-based strategy will be implemented 
for monitoring.  A combination of on-site and centralized monitoring may be performed. If 
systemic issues are identified during monitoring visits (i.e., consent process, ineligible 
participants, regulatory violations, missing data, etc.) re-training of the site staff will be 
suggested and the need for additional review will be assessed. A close out visit will be 
conducted once all participants have completed, withdrawn or been declared lost to follow-
up and all data queries have been resolved.  Any outstanding issues from previous 
monitoring reports will be reconciled.  
 
• 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The 
CMP describes in detail who will conduct the monitoring, at what frequency monitoring will 
be done, at what level of detail monitoring will be performed, and the distribution of 
monitoring reports. 
 
 
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
We will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  An individualized quality management plan will be 
developed to describe quality management.  
 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at CCHMC under the supervision of 
the PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   

 
 
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REMODEL 02.14.22 
 
Hardcopies of the study visit worksheets will be used as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into a REDCap data capture system 
provided by the CCHMC DCC. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.8.2 
STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonization (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention. These documents should be retained for a longer period, however, if required by 
local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents 
no longer need to be retained. 
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference 
on Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the CCHMC staff. As a result of deviations, corrective actions are to be developed and 
implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the PI to use continuous vigilance to identify and report deviations within 
3 working days of identification of the protocol deviation, or within five working days of the 
scheduled protocol-required activity.  All deviations must be addressed in study source 
documents and reported to the study Sponsor. Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The PI is responsible for knowing and adhering 
to the reviewing IRB requirements.  
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies 
and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-reviewed 

 
 
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journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information 
from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to 
publish results in peer-reviewed journals.  Data from this study may be requested from other 
researchers after the completion of the primary endpoint by contacting the CCHMC DCC. 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the Crohn’s and Colitis Foundation has 
established policies and procedures for all study group members to disclose all conflicts of interest 
and will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Not Applicable 
 
 
 
 
 
11 REFERENCES  
 
 
1. 
Dahlhamer JM, Zammitti EP, Ward BW, et al. Prevalence of Inflammatory Bowel Disease Among 
Adults Aged >/=18 Years - United States, 2015. MMWR Morb Mortal Wkly Rep 2016;65:1166-
1169. 
2. 
Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the 
treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007;132:863-73; 
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12 APPENDICES: 
 
Appendix A: Patient Reported Outcomes (Crohn’s Disease) 
Appendix B: Clinical Endoscopy Findings