REMODEL-CD: Precise Infliximab Exposure and Pharmacodynamic Control

Sponsor
Children's Hospital Medical Center, Cincinnati (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05660746
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
180
10
2
49.9
18
0.4

Study Details

Study Description

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).

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

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)

Study Design

Study Type:
Interventional
Anticipated Enrollment :
180 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Patients newly diagnosed with Crohn's disease (ages 6-22 years inclusive) within the last 90 days AND starting infliximabPatients newly diagnosed with Crohn's disease (ages 6-22 years inclusive) within the last 90 days AND starting infliximab
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease
Anticipated Study Start Date :
Feb 1, 2023
Anticipated Primary Completion Date :
Mar 31, 2027
Anticipated Study Completion Date :
Mar 31, 2027

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Conventional dosing

Induction Phase: 5-7.5 mg/kg at 0, 2, and 6 weeks. Maintenance Phase : 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.

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 activity scores and fecal calprotectin) with dosing support provided by the RoadMABTM clinical decision support tool.
Other Names:
  • Avsola
  • Inflectra
  • Ixifi
  • Remicade
  • Renflexis
  • Experimental: 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 activity scores and fecal calprotectin) with dosing support provided by the RoadMABTM clinical decision support tool.

    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 activity scores and fecal calprotectin) with dosing support provided by the RoadMABTM clinical decision support tool.
    Other Names:
  • Avsola
  • Inflectra
  • Ixifi
  • Remicade
  • Renflexis
  • Outcome Measures

    Primary Outcome Measures

    1. Rate of Deep Remission [Week 52]

      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

    Secondary Outcome Measures

    1. Rate of Steroid-free Clinical Remission [Week 14 and Week 52]

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

    2. Rate of Clinical Response [Week 14 and Week 52]

      Decrease from baseline pediatric Crohn's disease activity index (PCDAI) of at least 12.5 points & total PCDAI<30 or a PCDAI<10 (child) or a reduction of Crohn's disease activity index>70 from baseline or CDAI<150 (adult)

    3. Rate of Primary Clinical Nonresponse [Week 16]

      On prednisone >16 consecutive weeks from start of infliximab or a pediatric Crohn's disease activity index>30 or CDAI>220 for first four infusions

    4. Rate of Primary Biologic Nonresponse [Week 16]

      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)

    5. Rate of Sustained Steroid-free Remission [Week 22 - Week 52]

      Pediatric Crohn's disease activity index (PCDAI)<10 (child) or Crohn's disease activity index<150 (adult) at dose5 to week52 and off prednisone/budesonide from week 22-52

    6. Rate of Steroid-free Remission -biomarker composite [Week 14 and Week 52]

      Pediatric Crohn's disease activity index (PCDAI)<10 (child) or Crohn's disease activity index<150 (adult), off prednisone/budesonide for ≥4 weeks, CRP≤0.5 mg/dL and fecal calprotectin <250 μg/g3

    7. Rate of Endoscopic Healing [Week 52]

      Simple endoscopic score-Crohn's disease ≤2

    8. Rate of Complete Endoscopic Healing [Week 52]

      Simple endoscopic score-Crohn's disease=0

    9. Rate of Endoscopic Remission [Week 52]

      Simple endoscopic score-Crohn's disease<4

    10. Rate of Mucosal Healing [Week 52]

      Simple endoscopic score-Crohn's disease ≤2 and Ileal Global Histologic Activity Score (GHAS)/ Colon Global Histologic Activity Score (CGHAS) ≤2

    11. PK Model Bias [Week 0 - Week 84]

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

    12. PK Model Precision [Week 0 - Week 84]

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

    13. Rate of IBD related event - Fistula [Week 0 - Week 52]

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

    14. Rate of IBD related - Hospitalization [Week 0 - Week 52]

      Occurrence of Crohn's disease related hospitalization

    15. Rate of IBD related event - Surgery [Week 0 - Week 52]

      Occurrence of Crohn's disease related Surgery

    16. Rate of IBD related event - Intestinal stricture [Week 0 - Week 52]

      Occurrence of Crohn's disease related intestinal stricture

    17. Rate of IBD related event - Starting corticosteroids [Week 0 - Week 52]

      Occurrence of subjects starting a corticosteroid after week20

    18. Rate of IBD related event - Antibodies to infliximab [Week 0 - Week 52]

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

    19. Rate of Growth Restoration - Weight change [Week 14 - Week 52]

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

    20. Rate of Growth Restoration- Height velocity [Week 14 - Week 52]

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

    21. PK of infliximab in pediatric patients [Week 0 - Week 52]

      Measured infliximab clearance at baseline and at week52

    22. Correlation between infliximab induction exposure and endoscopic remission [Exposure Week 0 - Week 14, Efficacy Week 54]

      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 Simple Endoscopic Scorer Crohn's Disease (SES-CD) ≤2.

    23. Correlation between infliximab induction exposure and deep remission [Exposure Week 0 - Week 14, Efficacy Week 54]

      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 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) ≤2.

    24. Patient Reported Outcome-2 (PRO2) Response [Week 6, Week 14, Week 26, Week 52]

      defined as a >50% improvement in total score from baseline

    25. Patient Reported Outcome-2 (PRO2) Remission [Week 6, Week 14, Week 26, Week 52]

      defined as a stool frequency ≤3.0 and abdominal pain ≤1.0 (from baseline)

    26. Quality of Life & Disability -IMPACT-III score [Week 52]

      Total IMPACT-III (child) score

    27. Quality of Life & Disability - Inflammatory Bowel Disease Disk score [Week 52]

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

    28. Quality of Life & Disability - Short Inflammatory Bowel Disease score [Week 52]

      Total Short IBD Questionnaire (adult) score

    29. Process Evaluation -Usability of Decision Support Tool [Week 0 - Week 52]

      Total System Usability Scale score

    30. Rate of Adverse events [Week 0 - Week 52]

      Number of Adverse Events

    31. Rate of Serious Adverse events [Week 0 - Week 52]

      Number of Serious Adverse Events

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    6 Years to 22 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 60 days before the decision to start infliximab

    1. C-reactive protein >0.5 mg/dL in last 30 days and/or fecal calprotectin >250 μg/g within last 60 days before the decision to start infliximab

    2. 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. Clostridium difficile infection or other intestinal infection in the last 1-week or a severe infection in the last 90 days. Severe infection is defined as requiring hospitalization for treatment or a vancomycin taper.

    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 Any developmental disabilities that would impede providing assent/consent

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Los Angeles Los Angeles California United States 90027
    2 Lucile Packard Children's Hospital Stanford Palo Alto California United States 94304
    3 Rady Children's Hospital San Diego San Diego California United States 92123
    4 Nemours Children's Health System-Wilmington Wilmington Delaware United States 19803
    5 Nemours Children's Health System-Jacksonville Jacksonville Florida United States 32207
    6 Riley Hospital for Children Indianapolis Indiana United States 46202
    7 Cincinnati Children's Hospital Cincinnati Ohio United States 45229
    8 Cleveland Clinic Children's Hospital Cleveland Ohio United States 44106
    9 Nationwide Children's Hospital Columbus Ohio United States 43205
    10 Medical College of Wisconsin, Children's of Wisconsin Milwaukee Wisconsin United States 53226

    Sponsors and Collaborators

    • Children's Hospital Medical Center, Cincinnati
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    Investigators

    • Principal Investigator: Phillip Minar, MD,MS, Children's Hospital Medical Center, Cincinnati

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Children's Hospital Medical Center, Cincinnati
    ClinicalTrials.gov Identifier:
    NCT05660746
    Other Study ID Numbers:
    • 2022-0071
    • R01DK132408-01
    First Posted:
    Dec 21, 2022
    Last Update Posted:
    Dec 21, 2022
    Last Verified:
    Dec 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Children's Hospital Medical Center, Cincinnati
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Dec 21, 2022