Proactive Infliximab Optimization Using a PK Dashboard Versus SOC in Patients With Crohn's Disease: The OPTIMIZE Trial

• ClinicalTrials.gov Identifier: NCT04835506
• Recruitment Status: Enrolling by invitation
• First Posted: April 8, 2021
• Last Update Posted: April 6, 2023
• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: The Leona M. and Harry B. Helmsley Charitable Trust; Icahn School of Medicine at Mount Sinai
• Information provided by (Responsible Party): Adam Cheifetz, Beth Israel Deaconess Medical Center

Study Description

Brief 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 moderately to severely active CD.

Condition or disease	Intervention/treatment	Phase
Crohn Disease	Drug: Infliximab	Phase 4

Detailed Description:

Crohn's disease (CD) is a life-long chronic inflammatory bowel disease (IBD) characterized by transmural inflammation of the intestine. CD is a global disease in the 21st century with increasing incidence in newly industrialized countries. One of the most effective therapies to treat patients with moderate to severe CD 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 moderately to severely active CD. 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 196 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Crohn's Disease: The OPTIMIZE Trial
• Actual Study Start Date: November 1, 2021
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: December 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: proactive infliximab optimization; proactive infliximab optimization using a pharmacokinetic dashboard	Drug: Infliximab; infliximab
Experimental: standard of care infliximab dosing; standard of care infliximab dosing	Drug: Infliximab; infliximab

Outcome Measures

Primary Outcome Measures :

1. clinical remission [ Time Frame: 52 weeks ]
   Proportion of subjects with sustained corticosteroid-free (no corticosteroid (CS) use from Week 14 through 52) ) clinical remission (on the CDAI at Weeks 14, 26, 52) and no need for rescue therapy.

Secondary Outcome Measures :

1. clinical remission [ Time Frame: 52 weeks ]
   Proportion of subjects in CS-free clinical remission (CDAI <150 and no use of CS within previous 6 months)
2. deep remission [ Time Frame: 52 weeks ]
   Proportion of subjects in deep remission (CDAI < 150 and SES-CD ≤ 4, with no individual subscore > 1)
3. composite biological and endoscopic remission [ Time Frame: 52 weeks ]
   Proportion of subjects with a composite biological (hs-CRP<10 mg/L) and endoscopic remission (SES-CD ≤ 4)
4. sustained CS-free clinical remission [ Time Frame: 52 weeks ]
   4. Proportion of subjects with sustained CS-free clinical remission (CDAI <150 and no CS use from Week 14 through Week 52)
5. primary non-responders [ Time Frame: 14 weeks ]
   Proportion of subjects who are primary nonresponders (≤ 70-point decrease in CDAI score and at least one of: hs-CRP ≥10 mg/L, FC > 250 μg/g, or SES-CD > 4; or need for rescue therapy prior to Week 14)
6. biological remission [ Time Frame: 52 weeks ]
   Proportion of subjects with sustained biological remission (hs-CRP <10 mg/L)
7. endoscopic remission [ Time Frame: 52 weeks ]
   Proportion of subjects with endoscopic remission (SES-CD ≤ 4, with no individual subscore > 1)
8. hs-CRP normalization [ Time Frame: 52 weeks ]
   Proportion of subjects with normalization of hs-CRP (decrease from ≥ 10 at baseline to < 10 mg/L)
9. hs-CRP change from baseline [ Time Frame: week 14, week 26, and week 52 ]
   Hs-CRP change from baseline
10. endoscopic response [ Time Frame: 52 weeks ]
    Proportion of subjects with an endoscopic response (≥ 50% decrease from baseline SES-CD score)
11. fecal calprotectin [ Time Frame: 52 weeks ]
    Proportion of subjects with normalization of fecal calprotectin (decrease from >250 µg/g at baseline to ≤ 250 µg/g)
12. fecal calprotectin change [ Time Frame: 52 weeks ]
    fecal calprotectin change from baseline

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Males or nonpregnant, nonlactating females aged 16 to 80 years inclusive.
2. Diagnosis of CD prior to screening using standard endoscopic, histologic, or radiologic criteria. Subjects with patchy colonic inflammation initially diagnosed as indeterminate colitis would meet inclusion criteria, if the investigator feels that the findings are consistent with CD.

3. Moderately to severely active CD, defined by a total Crohn's Disease Activity Index (CDAI) score between 220 and 450 points, and at least 1 of the following:

   1. Elevated CRP > upper limit of normal )
   2. Elevated fecal calprotectin (FC) (> 250 μg/g)
   3. SES-CD > 6, or SES-CD > 3 for isolated ileal disease
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. Subjects with any of the following CD-related complications:

   1. Abdominal or pelvic abscess, including perianal
   2. Presence of stoma 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)
   7. Total colectomy.
2. History or current diagnosis of ulcerative colitis, 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.

Contacts and Locations

Locations

United States, Connecticut

Yale University School of Medicine

New Haven, Connecticut, United States, 06510

United States, Florida

University of Miami

Miami, Florida, United States, 33136

United States, Illinois

University of Chicago Medicine

Chicago, Illinois, United States, 60637

Northwestern University

Evanston, Illinois, United States, 60208

Rockford GI

Rockford, Illinois, United States, 61107

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, New Hampshire

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States, 03766

United States, New York

NYU Langone Health

New York, New York, United States, 10016

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

Weill Cornell Medical College

New York, New York, United States, 10065

United States, North Carolina

Atrium Health Center for Digestive Health

Charlotte, North Carolina, United States, 28204

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Rhode Island

LifeSpan Brown University

Providence, Rhode Island, United States, 02915

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 20500

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Beth Israel Deaconess Medical Center

The Leona M. and Harry B. Helmsley Charitable Trust

Icahn School of Medicine at Mount Sinai

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Papamichael K, Jairath V, Zou G, Cohen B, Ritter T, Sands B, Siegel C, Valentine J, Smith M, Vande Casteele N, Dubinsky M, Cheifetz A. Proactive infliximab optimisation using a pharmacokinetic dashboard versus standard of care in patients with Crohn's disease: study protocol for a randomised, controlled, multicentre, open-label study (the OPTIMIZE trial). BMJ Open. 2022 Apr 1;12(4):e057656. doi: 10.1136/bmjopen-2021-057656.

• Responsible Party: Adam Cheifetz, Professor of Medicine, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT04835506
• Other Study ID Numbers: 2021P000391
• First Posted: April 8, 2021
• Last Update Posted: April 6, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified participant data and trial-level data will be available on reasonable request. This data will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing agreement
• Time Frame: After completion and publication of primary study.
• Access Criteria: This data will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing agreement

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Crohn Disease; Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Infliximab; Tumor Necrosis Factor Inhibitors; Anti-Inflammatory Agents; Dermatologic Agents; Gastrointestinal Agents; Antirheumatic Agents