Clinical trial NCT05660746: Precise Infliximab Exposure and Pharmacodynamic Control
Official title: Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Crohn Disease
Keywords: Crohn's
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Janssen Scientific Affairs, LLC
First posted: 2022-12-21
Enrollment: 180
Sex: ALL
Minimum age (years): 6
Maximum age (years): 22
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients newly diagnosed with Crohn's disease (ages 6-22 years inclusive) within the last 90 days AND starting infliximab
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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)

Eligibility criteria: 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

Primary outcomes:
measure: Rate of Deep Remission
timeFrame: Week 52
Secondary outcomes:
measure: Rate of Steroid-free Clinical Remission
timeFrame: Week 14 and Week 52
measure: Rate of Clinical Response
timeFrame: Week 14 and Week 52
measure: Rate of Primary Clinical Nonresponse
timeFrame: Week 16
measure: Rate of Primary Biologic Nonresponse
timeFrame: Week 16
measure: Rate of Sustained Steroid-free Remission
timeFrame: Week 22 - Week 52
measure: Rate of Steroid-free Remission -biomarker composite
timeFrame: Week 14 and Week 52
measure: Rate of Endoscopic Healing
timeFrame: Week 52
measure: Rate of Complete Endoscopic Healing
timeFrame: Week 52
measure: Rate of Endoscopic Remission
timeFrame: Week 52
measure: Rate of Mucosal Healing
timeFrame: Week 52
measure: PK Model Bias
timeFrame: Week 0 - Week 52
measure: PK Model Precision
timeFrame: Week 0 - Week 52
measure: Rate of IBD related event - Fistula
timeFrame: Week 0 - Week 52
measure: Rate of IBD related - Hospitalization
timeFrame: Week 0 - Week 52
measure: Rate of IBD related event - Surgery
timeFrame: Week 0 - Week 52
measure: Rate of IBD related event - Intestinal stricture
timeFrame: Week 0 - Week 52
measure: Rate of IBD related event - Starting corticosteroids
timeFrame: Week 0 - Week 52
measure: Rate of IBD related event - Antibodies to infliximab
timeFrame: Week 0 - Week 52
measure: Rate of Growth Restoration - Weight change
timeFrame: Week 14 - Week 52
measure: Rate of Growth Restoration- Height velocity
timeFrame: Week 14 - Week 52
measure: PK of infliximab in pediatric patients
timeFrame: Week 0 - Week 52
measure: Correlation between infliximab induction exposure and endoscopic remission
timeFrame: Exposure Week 0 - Week 14, Efficacy Week 52
measure: Correlation between infliximab induction exposure and deep remission
timeFrame: Exposure Week 0 - Week 14, Efficacy Week 52
measure: Patient Reported Outcome-2 (PRO2) Response
timeFrame: Week 6, Week 14, Week 26, Week 52
measure: Patient Reported Outcome-2 (PRO2) Remission
timeFrame: Week 6, Week 14, Week 26, Week 52
measure: Quality of Life & Disability -IMPACT-III score
timeFrame: Week 52
measure: Quality of Life & Disability - Inflammatory Bowel Disease Disk score
timeFrame: Week 52
measure: Quality of Life & Disability - Short Inflammatory Bowel Disease score
timeFrame: Week 52
measure: Process Evaluation -Usability of Decision Support Tool
timeFrame: Week 0 - Week 52
measure: Rate of Adverse events
timeFrame: Week 0 - Week 52
measure: Rate of Serious Adverse events
timeFrame: Week 0 - Week 52
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Wilmington
country: United States
facility: Nemours Children's Health System-Wilmington
state: Delaware
city: Jacksonville
country: United States
facility: Nemours Children's Health System-Jacksonville
state: Florida
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Norfolk
country: United States
facility: Children's Specialty Group
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin, Children's of Wisconsin
state: Wisconsin
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Phillip Minar, MD,MS
role: PRINCIPAL_INVESTIGATOR
References: