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

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.

Inclusion criteria

• Males or nonpregnant, nonlactating females aged 16 to 80 years inclusive.
• 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).
• 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:

• Elevated CRP (> upper limit of normal)
• Elevated FC (> 250 μg/g)
• SES-CD > 6 (SES-CD > 3 for isolated ileal disease) for CD only and a Mayo endoscopic subscore (MES) ≥ 2 for UC only.
• Physician intends to prescribe IFX as part of the usual care of the subject.
• 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
• Able to participate fully in all aspects of this clinical trial.
• Written informed consent must be obtained and documented.

Exclusion criteria

• Participants with any of the following IBD-related complications:

• Abdominal or pelvic abscess, including perianal
• Presence of stoma, ileal pouch-anal anastomosis, or ostomy
• Isolated perianal disease
• Obstructive disease, such as obstructive stricture
• Short gut syndrome
• 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)
• Total colectomy.
• 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.
• 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.
• 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.
• Known primary or secondary immunodeficiency.
• PNR to adalimumab, defined as no objective evidence of clinical benefit after 14 weeks of therapy.
• 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.
• 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
• Presence of any medical condition or use of any medication that is a contraindication for IFX use, as outlined on the product label.
• 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.
• Pregnant or lactating women, to be excluded based on the physician's usual practice for determining pregnancy or lactation status.
• Known intolerance or hypersensitivity to IFX or other murine proteins.