Precise Infliximab Exposure and Pharmacodynamic Control

Crohn Disease Clinical Trial

— REMODEL-CD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05660746
• Other study ID #: 2022-0071
• Secondary ID: R01DK132408-01
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: July 1, 2023
• Est. completion date: March 31, 2027

Study information

• Verified date: March 2024
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: Phillip Minar, MD, MS
• Phone: 513-636-4415
• Email: phillip.minar[@]cchmc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: March 31, 2027
• Est. primary completion date: March 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 22 Years

Eligibility

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

Related Conditions & MeSH terms

• Crohn Disease

Intervention

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.

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Cleveland Clinic Children's Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Nemours Children's Health System-Jacksonville	Jacksonville	Florida
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	Medical College of Wisconsin, Children's of Wisconsin	Milwaukee	Wisconsin
United States	Lucile Packard Children's Hospital Stanford	Palo Alto	California
United States	Rady Children's Hospital San Diego	San Diego	California
United States	Nemours Children's Health System-Wilmington	Wilmington	Delaware

Sponsors (3)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati	Janssen Scientific Affairs, LLC, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Week 52
Secondary	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	Week 14 and Week 52
Secondary	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)	Week 14 and Week 52
Secondary	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	Week 16
Secondary	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)	Week 16
Secondary	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	Week 22 - Week 52
Secondary	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	Week 14 and Week 52
Secondary	Rate of Endoscopic Healing	Simple endoscopic score-Crohn's disease (SES-CD) =2	Week 52
Secondary	Rate of Complete Endoscopic Healing	SES-CD=0	Week 52
Secondary	Rate of Endoscopic Remission	SES-CD<4	Week 52
Secondary	Rate of Mucosal Healing	SES-CD=2 and Ileal Global Histologic Activity Score (GHAS)/ Colon Global Histologic Activity Score (CGHAS) =2	Week 52
Secondary	PK Model Bias	Model predicted vs. actual infliximab concentration. Bias: mean predictive error (MPE)	Week 0 - Week 52
Secondary	PK Model Precision	Model predicted vs. actual infliximab concentration. Precision: root mean squared error (RMSE)	Week 0 - Week 52
Secondary	Rate of IBD related event - Fistula	Occurrence of fistula and presence of antibody to infliximab >200 ng/mL	Week 0 - Week 52
Secondary	Rate of IBD related - Hospitalization	Occurrence of Crohn's disease related hospitalization	Week 0 - Week 52
Secondary	Rate of IBD related event - Surgery	Occurrence of Crohn's disease related surgery	Week 0 - Week 52
Secondary	Rate of IBD related event - Intestinal stricture	Occurrence of Crohn's disease related intestinal stricture	Week 0 - Week 52
Secondary	Rate of IBD related event - Starting corticosteroids	Occurrence of subjects starting a corticosteroid after week20	Week 0 - Week 52
Secondary	Rate of IBD related event - Antibodies to infliximab	Occurrence of antibodies to infliximab defined as >200 ng/mL	Week 0 - Week 52
Secondary	Rate of Growth Restoration - Weight change	In Tanner stage I-III subjects: change in baseline weight (kg) by gender and age group	Week 14 - Week 52
Secondary	Rate of Growth Restoration- Height velocity	In Tanner stage I-III subjects: change in height velocity (z-score) by gender	Week 14 - Week 52
Secondary	PK of infliximab in pediatric patients	Measured infliximab clearance at baseline and at week52	Week 0 - Week 52
Secondary	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.	Exposure Week 0 - Week 14, Efficacy Week 52
Secondary	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.	Exposure Week 0 - Week 14, Efficacy Week 52
Secondary	Patient Reported Outcome-2 (PRO2) Response	>50% improvement in total score from baseline	Week 6, Week 14, Week 26, Week 52
Secondary	Patient Reported Outcome-2 (PRO2) Remission	Stool frequency =3.0 and abdominal pain =1.0 (from baseline)	Week 6, Week 14, Week 26, Week 52
Secondary	Quality of Life & Disability -IMPACT-III score	Total IMPACT-III (child) score	Week 52
Secondary	Quality of Life & Disability - Inflammatory Bowel Disease Disk score	Total Inflammatory Bowel Disease Disk (without sexual function assessment) score	Week 52
Secondary	Quality of Life & Disability - Short Inflammatory Bowel Disease score	Total Short IBD Questionnaire (adult) score	Week 52
Secondary	Process Evaluation -Usability of Decision Support Tool	Total System Usability Scale score	Week 0 - Week 52
Secondary	Rate of Adverse events	Number of Adverse Events	Week 0 - Week 52
Secondary	Rate of Serious Adverse events	Number of Serious Adverse Events	Week 0 - Week 52