Precise Infliximab Exposure and Pharmacodynamic Control

Phase 3RecruitingNCT05660746

Children's Hospital Medical Center, Cincinnati180 enrolled

Overview

Approximately 3 million people in the United States are living with inflammatory bowel disease, which includes Crohn's Disease (CD). There are limited treatment options approved for use in children and adults with Crohn's disease. Physicians need better ways to inform decisions on treatment. The main reason for this research study is to determine if a computer program that calculates an individualized dose based on a patient's blood testing results (precision dosing) can better achieve the best possible response to infliximab compared to standard dosing (conventional dosing).

This is an open-label, cluster randomized clinical trial to test whether precision infliximab dosing with a targeted concentration intervention is superior in achieving deep remission (endoscopic healing and clinical remission) compared to patients receiving conventional infliximab dosing. With recognition that CD patients who achieve the "target" of deep remission with anti-TNF dose optimizations following pharmacodynamic monitoring had a significant reduction in CD-related adverse events, our central hypothesis is precision dosing with infliximab during induction and maintenance will achieve superior rates of deep remission vs. conventional care (control arm)

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

180

Conditions

Crohn Disease

Eligibility

Sex: ALLMin age: 6 YearsMax age: 22 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Written informed consent from the patient (≥18 years old) or from parent/legal guardian if patient is \<18 years old 2. Written informed assent from patient when age appropriate 3. Diagnosis of Crohn's disease within the last 90 days (luminal-only or luminal with a perianal fistula or abscess treated with antibiotics for at least 7 days) 4. ≥6 years to ≤22 years of age, anti-TNF naïve and starting infliximab 5. Clinical activity and luminal inflammation, defined by both (1) and (2) * (1) PCDAI≥10 (\<18 years old) or CDAI ≥150 (≥18 years old) in last 60 days before the decision to start infliximab * (2) SES-CD\>6, or SES-CD\>3 for isolated ileal disease (or a report of large intestinal ulcerations)\* within the last 60 days or a fecal calprotectin \>250 μg/g within last 75 days prior to screening 6. C-reactive protein \>1.0 mg/dL in last 30 days and/or fecal calprotectin \>250 μg/g within last 75 days prior to screening 7. Negative TB (tuberculosis) interferon-gamma release test and a negative urine pregnancy test for female patients (if menstruation has started) Exclusion Criteria: 1. Diagnosis of ulcerative colitis or inflammatory bowel disease-unspecified 2. Prior use of anti-TNF therapy (infliximab, adalimumab, certolizumab pegol, or golimumab) 3. Internal (abdominal/pelvic) penetrating fistula(e) in last 180 days 4. Intra-abdominal abscess/phlegmon/inflammatory mass in the last 180 days 5. Active perianal abscess (receiving oral antibiotics for \<7 days) 6. Intestinal stricture (luminal narrowing with pre-stenotic dilation \>3 cm) and surgery planned in the next 90 days 7. Have tested positive for Clostridium difficile toxin (stool assay) or other intestinal pathogens within 14 days of screening unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen. 8. Current hospitalization for complications of severe Crohn's disease 9. Planned use of methotrexate or 6-mercaptopurine (azathioprine) during the induction (first 3 doses of infliximab) phase 10. Current ileostomy, colostomy, ileoanal pouch, and/or previous extensive small bowel resection (\>35 cm) or any CD surgery planned within the next 90 days 11. History of autoimmune hepatitis, primary sclerosing cholangitis, thyroiditis, or juvenile idiopathic arthritis 12. Treatment with another investigational drug in the last four weeks 13. History of malignancy (including lymphoma or leukemia) 14. Currently receiving treatment for histoplasmosis 15. History of TB, human immunodeficiency virus (HIV), an immunodeficiency syndrome, a central nervous system demyelinating disease, history of heart failure or receiving intravenous antibiotics in last 14 days for any infection 16. Currently pregnant, breast feeding or plans to become pregnant in the next 1 year 17. Inability or failure to provide informed assent/consent 18. Any developmental disabilities that would impede providing assent/consent

Outcomes

Primary Outcomes

Rate of Deep Remission

Pediatric Crohn's disease activity index (PCDAI) \<10 (child) or Crohn's disease activity index\<150 (adult), off prednisone/budesonide for \>8 weeks and Simple Endoscopic Scorer Crohn's Disease (SES-CD) SES-CD≤2

Time frame: Week 52

Secondary Outcomes

Rate of Steroid-free Clinical Remission

Pediatric Crohn's disease activity index (PCDAI) \<10 (child) or Crohn's disease activity index(CDAI)\<150 (adult) and off prednisone/budesonide for ≥4 weeks

Time frame: Week 14 and Week 52

Rate of Clinical Response

Decrease from baseline PCDAI of at least 12.5 points \& total PCDAI\<30 or a PCDAI\<10 (child) or a reduction of CDAI\>70 from baseline or CDAI\<150 (adult)

Time frame: Week 14 and Week 52

Rate of Primary Clinical Nonresponse

On prednisone \>16 consecutive weeks from start of infliximab or a PCDAI\>30 or CDAI\>220 for first four infusions

Time frame: Week 16

Rate of Primary Biologic Nonresponse

Failure to improve baseline fecal calprotectin by \>100 μg/g (limited to patients with a baseline fecal calprotectin \>250 μg/g) or Failure to improve baseline c-reactive protein ≥0.5 mg/dL (limited to patients with a baseline c-reactive protein \>1.0 mg/dL)

Time frame: Week 16

Rate of Sustained Steroid-free Remission

PCDAI\<10 (child) or CDAI\<150 (adult) at dose5 to week52 and off prednisone/budesonide from week 22-52

Time frame: Week 22 - Week 52

Rate of Steroid-free Remission -biomarker composite

PCDAI\<10 (child) or CDAI\<150 (adult), off prednisone/budesonide for ≥4 weeks, CRP≤0.5 mg/dL and fecal calprotectin \<250 μg/g

Time frame: Week 14 and Week 52

Rate of Endoscopic Healing

Simple endoscopic score-Crohn's disease (SES-CD) ≤2

Time frame: Week 52

Rate of Complete Endoscopic Healing

SES-CD=0

Time frame: Week 52

Rate of Endoscopic Remission

SES-CD\<4

Time frame: Week 52

Rate of Mucosal Healing

SES-CD≤2 and Ileal Global Histologic Activity Score (GHAS)/ Colon Global Histologic Activity Score (CGHAS) ≤2

Time frame: Week 52

PK Model Bias

Model predicted vs. actual infliximab concentration. Bias: mean predictive error (MPE)

Time frame: Week 0 - Week 52

PK Model Precision

Model predicted vs. actual infliximab concentration. Precision: root mean squared error (RMSE)

Time frame: Week 0 - Week 52

Rate of IBD related event - Fistula

Occurrence of fistula and presence of antibody to infliximab \>200 ng/mL

Time frame: Week 0 - Week 52

Rate of IBD related - Hospitalization

Occurrence of Crohn's disease related hospitalization

Time frame: Week 0 - Week 52

Rate of IBD related event - Surgery

Occurrence of Crohn's disease related surgery

Time frame: Week 0 - Week 52

Rate of IBD related event - Intestinal stricture

Occurrence of Crohn's disease related intestinal stricture

Time frame: Week 0 - Week 52

Rate of IBD related event - Starting corticosteroids

Occurrence of subjects starting a corticosteroid after week20

Time frame: Week 0 - Week 52

Rate of IBD related event - Antibodies to infliximab

Occurrence of antibodies to infliximab defined as \>200 ng/mL

Time frame: Week 0 - Week 52

Rate of Growth Restoration - Weight change

In Tanner stage I-III subjects: change in baseline weight (kg) by gender and age group

Time frame: Week 14 - Week 52

Rate of Growth Restoration- Height velocity

In Tanner stage I-III subjects: change in height velocity (z-score) by gender

Time frame: Week 14 - Week 52

PK of infliximab in pediatric patients

Measured infliximab clearance at baseline and at week52

Time frame: Week 0 - Week 52

Correlation between infliximab induction exposure and endoscopic remission

The correlation analysis to be performed for the total area under the curve (infliximab exposure, μg\*h/mL from week0-week14) and patients achieving endoscopic remission. Endoscopic remission is defined as a SES-CD≤2.

Time frame: Exposure Week 0 - Week 14, Efficacy Week 52

Correlation between infliximab induction exposure and deep remission

The correlation analysis to be performed for the total area under the curve (infliximab exposure, μg\*h/mL from week0-week14) and patients in deep remission. Deep remission is defined as a PCDAI\<10 (child) or CDAI\<150 (adult), off prednisone/budesonide for \>8 weeks and a SES-CD≤2.

Time frame: Exposure Week 0 - Week 14, Efficacy Week 52

Patient Reported Outcome-2 (PRO2) Response

\>50% improvement in total score from baseline

Time frame: Week 6, Week 14, Week 26, Week 52

Patient Reported Outcome-2 (PRO2) Remission

Stool frequency ≤3.0 and abdominal pain ≤1.0 (from baseline)

Time frame: Week 6, Week 14, Week 26, Week 52

Quality of Life & Disability -IMPACT-III score

Total IMPACT-III (child) score

Time frame: Week 52

Quality of Life & Disability - Inflammatory Bowel Disease Disk score

Total Inflammatory Bowel Disease Disk (without sexual function assessment) score

Time frame: Week 52

Quality of Life & Disability - Short Inflammatory Bowel Disease score

Total Short IBD Questionnaire (adult) score

Time frame: Week 52

Process Evaluation -Usability of Decision Support Tool

Total System Usability Scale score

Time frame: Week 0 - Week 52

Rate of Adverse events

Number of Adverse Events

Time frame: Week 0 - Week 52

Rate of Serious Adverse events

Number of Serious Adverse Events

Time frame: Week 0 - Week 52

Precise Infliximab Exposure and Pharmacodynamic Control

Overview

Conditions

Interventions

Eligibility

Locations (11)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts