IDeaL Pilot Study - Infliximab Dose to Level: Pilot Study
Condition: Inflammatory Bowel Disease; Crohn's Disease
MeSH terms: Crohn Disease; Inflammatory Bowel Diseases
Study type: Observational

Summary: 
      Crohn's disease (CD) is a lifelong condition of inflammation in the bowel. CD can affect any
      part of the gastrointestinal tract from mouth to anus. Symptoms can include: tiredness,
      stomach pain, diarrhea (which may be bloody if the disease is severe), fever, weight loss,
      skin rashes, arthritis and inflammation of the eye.

      Infliximab-IFX (Remicade®) is a medication that is used to treat CD in adults and children.
      In adults it has been shown that the amount of this drug a person has in their blood can show
      how well it is working for them. Health Canada has approved Infliximab -IFX for the treatment
      of CD in children 9 and older. In Canada, doctors may prescribe Inflixmab to younger children
      when other therapies do not resolve their disease symptoms. This is called "off-label" use of
      Infliximab.

      IFX levels in the body and consequently its efficacy can be influenced by many biological
      characteristics within the patient's body. In about 17% of those treated with IFX, the
      patient's immune response against IFX may lead to a three to fivefold increased risk of loss
      of response. This immune response to the medication often occurs when drug levels are
      undetectable in the body. Thus it is in order to achieve best results with this treatment,
      physicians need to be able to adjust dosing specific to each patient. A recent study has
      shown that 29% of children have an undetectable IFX level at the 4th medication infusion. Up
      to 40% of patients receiving scheduled IFX have undetectable drug level prior to their next
      infusion.

      In order to minimize the loss of response, we hope to conduct an observational cohort study
      of pediatric patients treated with IFX.

      This open label, cohort study aims to:

        1. Determine the pharmacokinetics of IFX in children with CD and the factors that affect
           IFX levels during the first three loading infusions

        2. Obtain data to create a model that can guide and adjust the IFX dose and frequency to
           achieve optimal trough level between 5 and 10 ug /ml at 14 weeks.
    

Detailed description: 
      Crohn's disease (CD) is a chronic inflammatory bowel disease characterized by inflammation
      that can affect any part of the gastrointestinal tract from mouth to anus. Other
      complications may occur outside the gastrointestinal tract and include: anemia, skin rashes,
      arthritis, inflammation of the eye, and tiredness. Symptoms often include: abdominal pain,
      diarrhea (which may be bloody if inflammation is severe), fever and weight loss. Crohn's
      disease is caused by a combination of environmental, immune and bacterial factors in
      genetically susceptible individuals. It results in a chronic inflammatory disorder, in which
      the body's immune system attacks the gastrointestinal tract possibly directed at microbial
      antigens. The estimated prevalence of CD in Canada is 234 per 100,000 persons, with an
      incidence rate of 13.4 per 100,000. There are no medications or surgical procedures that can
      cure Crohn's disease. Treatment options help with symptoms, maintain remission, and prevent
      relapse. The burden of disease is high with disease flares and complications leading to
      hospitalizations, surgeries, school and work absenteeism, and impaired quality of life.

      Infliximab (IFX) is a murine chimeric lgGl anti-TNFa monoclonal antibody shown in landmark
      clinical trials to be well-tolerated and effective for induction, and maintenance, of
      remission in pediatric and adult CD and ulcerative colitis. In Canada, the safety and
      efficacy of IFX is not established in children under the age of 9, yet is often prescribed to
      younger children off label when other therapies do not resolve their disease symptoms. IFX
      can be influenced by multiple factors such as body mass index (BMI), serum albumin level,
      burden of inflammation and the concomitant use of immunosuppressive medications. Loss of
      response to IFX can either be a result of Antibodies to IFX (ATI) or insufficient serum IFX
      level.

      ATI have been shown to develop in about 17% of those treated with IFX. The risk for
      development of ATI is even higher in those who receive IFX mono-therapy, compared to those
      receiving concomitant immunomodulator. It is now clear that those with persistent ATI have a
      three to fivefold increased risk of loss of response to IFX compared to those without ATI.
      ATI appears to interfere with the bioactivity of IFX and those patients who develop ATI are
      more likely to subsequently manifest infusion reactions, including anaphylaxis.

      The standard infusion regimen for IFX is three loading dose of 5mg/kg (dose is often rounded
      up to the nearest 100mg) at 0, 2, 6 weeks then every 8 weeks thereafter. The trough level of
      IFX after the 3rd loading dose (week 14 - i.e. before the 4th infusion) is often found to be
      at greatest risk of being low; especially in children.

      A recent study has shown that 29% of children have an undetectable IFX level at the 4th
      medication infusion. A trough level of 5 ug /ml at this time point is associated with higher
      remission rates. Conversely, a low trough level (< 2.2 ug/ml) at week 14 predicts IFX
      discontinuation. Up to 40% of patients receiving scheduled IFX have undetectable drug level
      prior to their next infusion. However, whether having undetectable IFX level at trough
      increases the risk of ATI formation is currently unclear. Moreover, it is unknown if dosing
      adjustments based on trough levels will change rates of antibody formation to IFX and the
      sustained efficacy of IFX nor how we can achieve desired serum levels at clinically relevant
      time-points, mainly because the pharmacokinetics of IFX in children has not been well
      studied.

      Most trials assessing IFX trough levels and ATI have been performed retrospectively. A recent
      meta-analysis of the impact of ATI and IFX level in IBD showed that the presence of ATI is
      associated with a significantly higher risk of loss of clinical response to IFX and lower
      serum IFX levels in patients with IBD. One prospective trial of 270 adult IBD patients who
      were in remission on IFX maintenance therapy had their regimen modified to achieve trough IFX
      level between 3-7 ug/ml, and were then randomized to further dosing and optimization
      adjustments based on IFX trough levels - level-based (LB) - or on clinical symptoms (CB}. The
      primary endpoint of remission after 1 year was similar at 70%. ATI was 0 with LB and 2.7%
      with CB. However, 17% of CB required rescue therapy with either corticosteroids, increased
      doses of IFX or a switch to another Anti-TNFa (Vande Casteele UEGW 2013 Abstract). There are
      currently no prospective studies in pediatric patients to assess a treat-to-level of IFX
      strategy in Crohn's disease.

      Several authors have suggested that a median trough level of > 3 ug/ml (range 2.3 to 4.9) is
      associated with maintenance of remission. However this value tends to reflect the limit of
      detection of the assay used rather than the actual biologic threshold. Lamblin reported a
      higher IFX level of 6.33ug /ml to be associated with higher remission rates compared to a
      level of 3.39 ug /ml. Based on these authors' modeling, a level 5.6 ug /ml would lead to
      lower inflammatory burden based on C reactive protein (CRP} < 5 ug /ml. In the most recent
      largest retrospective study on IFX in Inflammatory Bowel Disease (IBD) patients (n=l36},
      Arias reported that a level of 7.9 ug /ml gave a 57% sensitivity and 80% specificity for
      predicting best sustained response to IFX. Based on the above data we hypothesize that the
      ideal trough level is likely between 5 and 10 ug /ml. The upper range of this trough level
      range is very close to the upper interquartile range in the Arias' study.

      A further barrier to knowledge advancement emanates from recent changes in laboratory
      techniques used to assess serum IFX levels and ATI. A private laboratory in the United
      States, Prometheus, had previously been the only accessible laboratory where clinicians could
      obtain serum IFX and ATI levels using an enzyme-linked immuno sorbent assay (ELISA).
      Recently, they stopped performing the ELISA test and moved to an extremely expensive
      homogeneous mobility shift assay (HMSA) for the measurement of IFX and ATI. The advantage of
      this new test is the ability to detect the presence of ATI and IFX in the serum at the same
      time. With the previous ELISA test, ATI were not measurable in the presence of IFX, thus ATI
      status was typically labeled as "inconclusive" in this setting. Despite these advantages,
      there is currently no evidence to justify the use more sensitive but expensive HMSA test in
      the clinical setting and in particular there is no supporting evidence to warrant the use of
      this test as part of treat to level strategy.

      At a time when therapeutic drug monitoring of IFX and precision dosing of biologic agents are
      becoming increasingly hot topics, Alberta Health Services has refused to pay for HMSA testing
      in patients treated with IFX because of the exorbitant costs. In an attempt to overcome this
      barrier to precision care, the biochemistry laboratory at the University Hospital (UAH),
      under the leadership of Dr Connie Prosser, has developed a locally developed (ELISA) for IFX
      level and ATI at a fraction of the cost charged by Prometheus ($50 for IFX level and $50 for
      ATI- total $100 for both tests compared to US $2500 for both IFX and ATI per test). The UAH
      test has been validated in a local study and was able to measure the IFX level down to 0.4
      ug/ml, with very good inter- and intra- assay precision. Based on patient samples, the
      correlation between the UAH test and the HMSA results is excellent (R2= 0.92 for values
      ranging from <0.4 ug/ml to >45 ug/ml and R2 = 0.98 for values <20 ug/ml). ATI (unbound) can
      be measured at levels ≥ 2 ug/ml in samples having an IFX concentration < 10 ug/ml. A second
      ELISA is available which measures total ATI (i.e. free and bound to circulating IFX), and can
      detect antibody in samples with higher IFX concentrations if needed. This test is now
      available for clinical use in the Edmonton Zone. However the current indication for the test
      is only for those patients who exhibit clinical loss of response to IFX. Dose Optimization is
      common, 70% of us dose optimize clinically. Early dose optimization after third infusion
      likely to be better. How to dose optimize is unclear.
    

Intervention name(s): Infliximab
Intervention type(s): Biological
Intervention description(s): Patients will be prescribed Infliximab as a standard of care regardless of study participation.
Other intervention name(s): Remicade
Intervention MeSH terms: Infliximab
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Pediatric patients with Crohn's Disease whose treating physician has planned to start IFX
        for treatment of their CD.
      
Biospecimen description: 
      Blood will be collected to determine IFX levels and serum cytokines. Stool will be collected
      for calprotectin. Urine will be collected for metabolomics.

      If a child undergoes endoscopy or surgery during the 8 weeks after beginning IFX, a specimen
      will be collected for tissue cytokine assay.
    
Keywords: IBD; Crohn's disease; Remicade; Infliximab; Level; Drug Level; Children