Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial

Ulcerative Colitis Clinical Trial

Official title:

Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04835506
• Other study ID #: 2021P000391
• Status: Enrolling by invitation
• Phase: Phase 4
• Start date: November 1, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: January 2024
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The OPTIMIZE Trial compares whether iDose dashboard-driven infliximab dosing (iDose-driven dosing) is more effective and safer than standard infliximab dosing for inducing and maintaining disease remission in inflammatory bowel disease.

Description:

Inflammatory bowel disease (IBD), namely Crohn's disease (CD) and ulcerative colitis (UC) are life-long chronic diseases characterized by transmural inflammation of the intestine. CD and UC are global diseases in the 21st century with increasing incidence in newly industrialized countries. One of the most effective therapies to treat patients with moderate to severe disease is the antitumor necrosis factor (TNF) agent infliximab (IFX) either as monotherapy or as a combination therapy with an immunomodulator (IMM), such as azathioprine or methotrexate (MTX).

Although more effective, combination therapy is associated with more serious adverse events, such as serious opportunistic infections and cancers, as well as potential treatment adherence issues. Consequently, many patients and physicians choose to use IFX alone as safety is often prioritized over efficacy. Unfortunately, up to 30% of patients do not respond to induction therapy, and up to 50% of initial responders lose response over time. It is only if patients lose response that physicians check blood IFX concentrations (i.e., reactive therapeutic drug monitoring [TDM]), or empirically increase IFX dose. Reactive TDM helps to explain and better manage these patients with lack or loss of response to IFX. In many cases, the lack or LOR is due to low drug concentrations with or without development of antibodies to IFX (ATI). Unfortunately, reactive TDM or empiric dose escalation is often too late for patients who do not either respond to IFX induction therapy or lose response during maintenance. This reactive approach results in many patients losing IFX as a therapeutic option.

Preliminary data show that proactive IFX optimization to achieve a threshold drug concentration during maintenance therapy (even if the patient is asymptomatic) compared to empiric dose escalation and/or reactive TDM is associated with better long-term outcomes including longer drug persistence, reduced risk of relapse, and fewer hospitalizations and surgeries. IFX dosing by weight only (i.e., mg/kg) may not be adequate for many patients as interindividual variability in drug clearance and other factors affecting IFX concentrations and PK are often not accounted for. Dosing calculators take into account all of these individual factors and improve the precision of dosing towards better personalized medicine. These systems have already been validated, and personalized dosing has shown clinical benefit in patients with IBD.

This is a randomized, controlled, multicenter, open-label study that plans to enroll 196 participants with inflammatory bowel disease. All eligible participants will be randomly assigned in a 1:1 ratio to receive either IFX monotherapy with proactive TDM or SOC IFX therapy, with or without concomitant IMM therapy, and empiric dose optimization or reactive TDM, at the discretion of the investigator.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 196
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

1. Males or nonpregnant, nonlactating females aged 16 to 80 years inclusive.

2. Diagnosis of IBD prior to screening using standard endoscopic, histologic, or radiologic criteria. Participants with patchy colonic inflammation initially diagnosed as indeterminate colitis would meet inclusion criteria, if the investigator feels that the findings are consistent with CD or UC. Enrollment of participants with UC will be capped at 49% of the planned study population (maximum 61 participants).

3. Moderately to severely active IBD, defined by a total CDAI score between 220 and 450 points for CD or a partial Mayo Score (PMS) > 4 for UC (including a rectal bleeding subscore [RBS] = 1), and at least 1 of the following:

1. Elevated CRP (> upper limit of normal)

2. Elevated FC (> 250 µg/g)

3. SES-CD > 6 (SES-CD > 3 for isolated ileal disease) for CD only and a Mayo endoscopic subscore (MES) = 2 for UC only.

4. Physician intends to prescribe IFX as part of the usual care of the subject.

5. No previous use of IFX prior to enrolment in the current study, unless the participant received 1 prior dose of IFX (within 2.5 weeks of enrolment) and met all eligibility criteria at the time of starting IFX and IFX was administered according to the requirements outlined in this protocol

6. Able to participate fully in all aspects of this clinical trial.

7. Written informed consent must be obtained and documented.

Exclusion Criteria:

1. Participants with any of the following IBD-related complications:

1. Abdominal or pelvic abscess, including perianal

2. Presence of stoma, ileal pouch-anal anastomosis, or ostomy

3. Isolated perianal disease

4. Obstructive disease, such as obstructive stricture

5. Short gut syndrome

6. Toxic megacolon or any other complications that might require surgery, or any other manifestation that precludes or confounds the assessment of disease activity (CDAI or SES-CD for CD or PMS, PRO2, or MES for UC)

7. Total colectomy.

2. History or current diagnosis of ulcerative proctitis (UC extending < 15 cm from the anal verge), acute severe (fulminant) UC, hospitalised IV steroid-refractory UC, indeterminate colitis, microscopic colitis, ischemic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption.

3. Current bacterial or parasitic pathogenic enteric infection, according to SOC assessments, including: Clostridioides difficile; tuberculosis; known infection with hepatitis B or C virus; known infection with HIV; sepsis; abscesses. History of the following: opportunistic infection within 6 months prior to screening; any infection requiring antimicrobial therapy within 2 weeks prior to screening; more than 1 episode of herpes zoster or any episode of disseminated zoster; any other infection requiring hospitalization or intravenous antimicrobial therapy within 4 weeks prior to screening.

4. Has any malignancy or lymphoproliferative disorder other than nonmelanoma cutaneous malignancies or cervical carcinoma in situ that has been treated with no evidence of recurrence within the last 5 years.

5. Known primary or secondary immunodeficiency.

6. PNR to adalimumab, defined as no objective evidence of clinical benefit after 14 weeks of therapy.

7. Subjects with failure to a prior biologic, defined as PNR or SLR, will be excluded when a maximum of 40% of the planned enrollment (approximately 78 subjects) have failure to prior biologic exposure.

8. Concomitant use of oral corticosteroid therapy exceeding prednisone 40 mg/day, budesonide 9 mg/day, or equivalent, unless a tapering schedule is initiated with a plan to be off CS by Week 14

9. Presence of any medical condition or use of any medication that is a contraindication for IFX use, as outlined on the product label.

10. A concurrent clinically significant, serious, unstable, or uncontrolled underlying cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, might confound the study results, pose additional risk to the subject, or interfere with the subject's ability to participate fully in the study.

11. Pregnant or lactating women, to be excluded based on the physician's usual practice for determining pregnancy or lactation status.

12. Known intolerance or hypersensitivity to IFX or other murine proteins.

Related Conditions & MeSH terms

• Crohn Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Ulcerative Colitis

Intervention

Drug:
• Infliximab
infliximab

Locations

Country	Name	City	State
Canada	London Health Sciences Centre - Children's Hospital	London
Canada	McGill University Health Centre (MUHC) Montreal General Hospital	Montreal
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Atrium Health Center for Digestive Health	Charlotte	North Carolina
United States	University of Chicago Medicine	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Northwestern University	Evanston	Illinois
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	NYU Langone Health	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	LifeSpan Brown University	Providence	Rhode Island
United States	Rockford GI	Rockford	Illinois
United States	University of Utah	Salt Lake City	Utah

Sponsors (3)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Icahn School of Medicine at Mount Sinai, The Leona M. and Harry B. Helmsley Charitable Trust

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	clinical remission	Proportion of subjects with sustained corticosteroid-free (no CS use from Week 14 through 52) clinical remission (CD: CDAI <150 at Weeks 14, 26, 52; UC: PRO2 = 1 with an RBS = 0) and no disease worsening	52 weeks
Secondary	clinical remission	Proportion of subjects in CS-free clinical remission (CD: CDAI < 150; UC: PRO2 = 1 with an RBS = 0) and no use of CS within previous 6 months)	52 weeks
Secondary	deep remission	Proportion of subjects in deep remission (CD: CDAI < 150 and SES-CD = 4, with no individual subscore > 1; UC: PRO2 = 1 with an RBS = 0 and MES = 1)	52 weeks
Secondary	composite biological and endoscopic remission	Proportion of subjects with a composite biological (hs-CRP < 10 mg/L) and endoscopic remission (CD: SES-CD = 4; UC: MES = 1)	52 weeks
Secondary	sustained CS-free clinical remission	Proportion of subjects with sustained CS-free clinical remission (CD: CDAI < 150; UC: PRO2 = 1 with an RBS = 0) and no CS use or need for rescue therapy from Week 14 through Week 52)	52 weeks
Secondary	primary non-responders	Proportion of subjects who are primary nonresponders (= 70-point decrease in CDAI score or lack of a = 1-point and 30% reduction from baseline in PRO2 and a = 1-point reduction in RBS or an absolute RBS = 1 for UC and at least one of: hs-CRP =10 mg/L, FC > 250 µg/g, or SES-CD > 4 or MES > 1 for UC, or disease worsening prior to Week 14)	14 weeks
Secondary	biological remission	Proportion of subjects with sustained biological remission (hs-CRP <10 mg/L)	52 weeks
Secondary	endoscopic remission	Proportion of subjects with endoscopic remission (SES-CD = 4, with no individual subscore > 1 for CD or MES = 1 for UC)	52 weeks
Secondary	hs-CRP normalization	Proportion of subjects with normalization of hs-CRP (decrease from = 10 at baseline to < 10 mg/L)	52 weeks
Secondary	hs-CRP change from baseline	Hs-CRP change from baseline	week 14, week 26, and week 52
Secondary	endoscopic response	Proportion of subjects with an endoscopic response (CD: = 50% decrease from baseline SES-CD score; UC: = 1-point decrease in MES)	52 weeks
Secondary	fecal calprotectin	Proportion of subjects with normalization of fecal calprotectin (decrease from >250 µg/g at baseline to = 250 µg/g)	52 weeks
Secondary	fecal calprotectin change	fecal calprotectin change from baseline	52 weeks