Precise Infliximab Exposure and Pharmacodynamic Control

Official title

Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease

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).

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)

Interventions

• Device RoadMAB
  The RoadMAB Dashboard is a real-time decision support system that incorporates PK model-informed Bayesian estimation to provide precision dosing at the point of care.
• Drug Infliximab
  Conventional dosing. Induction: 5-7.5 mg/kg at 0, 2, and 6 weeks. Maintenance: 5-10 mg/kg at every 4-8 weeks based on results of drug concentration monitoring for a flat target of 5-10 μg/mL. Precision dosing. Induction: 5-12.5 mg/kg at 0, 2, and 6 weeks to target a week6 concentration of 18-24 μg/mL with dosing support provided by the RoadMABTM clinical decision support tool. Maintenance: 5-15 mg/kg every 4-8 weeks to achieve apriori pharmacokinetic and pharmacodynamic targets (CRP, disease ac

Primary outcome measures

• Rate of Deep Remission [Time frame: Week 52]

Secondary outcome measures (12)

• Rate of Steroid-free Clinical Remission [Time frame: Week 14 and Week 52]
• Rate of Clinical Response [Time frame: Week 14 and Week 52]
• Rate of Primary Clinical Nonresponse [Time frame: Week 16]
• Rate of Primary Biologic Nonresponse [Time frame: Week 16]
• Rate of Sustained Steroid-free Remission [Time frame: Week 22 - Week 52]
• Rate of Steroid-free Remission -biomarker composite [Time frame: Week 14 and Week 52]
• Rate of Endoscopic Healing [Time frame: Week 52]
• Rate of Complete Endoscopic Healing [Time frame: Week 52]
• Rate of Endoscopic Remission [Time frame: Week 52]
• Rate of Mucosal Healing [Time frame: Week 52]
• PK Model Bias [Time frame: Week 0 - Week 52]
• PK Model Precision [Time frame: Week 0 - Week 52]

Eligibility criteria

Inclusion criteria

• Written informed consent from the patient (≥18 years old) or from parent/legal guardian if patient is <18 years old
• Written informed assent from patient when age appropriate
• 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)
• ≥6 years to ≤22 years of age, anti-TNF naïve and starting infliximab
• 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
• 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
• Negative TB (tuberculosis) interferon-gamma release test and a negative urine pregnancy test for female patients (if menstruation has started)

Exclusion criteria

• Diagnosis of ulcerative colitis or inflammatory bowel disease-unspecified
• Prior use of anti-TNF therapy (infliximab, adalimumab, certolizumab pegol, or golimumab)
• Internal (abdominal/pelvic) penetrating fistula(e) in last 180 days
• Intra-abdominal abscess/phlegmon/inflammatory mass in the last 180 days
• Active perianal abscess (receiving oral antibiotics for <7 days)
• Intestinal stricture (luminal narrowing with pre-stenotic dilation >3 cm) and surgery planned in the next 90 days
• 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.
• Current hospitalization for complications of severe Crohn's disease
• Planned use of methotrexate or 6-mercaptopurine (azathioprine) during the induction (first 3 doses of infliximab) phase
• Current ileostomy, colostomy, ileoanal pouch, and/or previous extensive small bowel resection (>35 cm) or any CD surgery planned within the next 90 days
• History of autoimmune hepatitis, primary sclerosing cholangitis, thyroiditis, or juvenile idiopathic arthritis
• Treatment with another investigational drug in the last four weeks
• History of malignancy (including lymphoma or leukemia)
• Currently receiving treatment for histoplasmosis
• 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
• Currently pregnant, breast feeding or plans to become pregnant in the next 1 year
• Inability or failure to provide informed assent/consent
• Any developmental disabilities that would impede providing assent/consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 11 centers

• Children's Hospital of Los Angeles — Los Angeles
• Lucile Packard Children's Hospital Stanford — Palo Alto
• Rady Children's Hospital San Diego — San Diego
• Nemours Children's Health System-Wilmington — Wilmington
• Nemours Children's Health System-Jacksonville — Jacksonville
• Riley Hospital for Children — Indianapolis
• Cincinnati Children's Hospital — Cincinnati
• Cleveland Clinic Children's Hospital — Cleveland
• … and 3 more centers

Publications

• Minar PP, Colman RJ, Zhang N, Mizuno T, Vinks AA. Precise infliximab exposure and pharmacodynamic control to achieve deep remission in paediatric Crohn's disease (REMODEL-CD): study protocol for a multicentre, open-label, pragmatic clinical trial in the USA. BMJ Open. 2024 Mar 25;14(3):e077193. doi: 10.1136/bmjopen-2023-077193. PMID 38531570

Identifiers

NCT: NCT05660746 · 2022-0071 · R01DK132408-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗