A Trial of Iron Replacement in Patients With Iron Deficiency.
Condition: Iron Deficiency; Inflammatory Bowel Disease
MeSH terms: Intestinal Diseases; Inflammatory Bowel Diseases; Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Interventional
Phase: Phase 4

Summary: 
      Primary Hypothesis: There is no difference in the efficacy of iron replacement by oral or
      intravenous route in Inflammatory Bowel Disease patients.

      Iron deficiency anaemia is a common problem in people with inflammatory bowel disease (IBD)
      and patients with excessive blood loss from the bowel or heavy menstrual loss. Treatment
      options include a blood transfusion, oral iron with (Ferrograd ®) or intravenous iron
      replacement with iron sucrose (Venofer®). Iron deficiency anaemia is associated with poor
      quality of life, poor concentration span and low energy level. Blood transfusion may improve
      symptomatic anaemia quickly but there is a risk of transfusion reaction and blood born
      infection transmission. Moreover, packed cells are scarce resource therefore its use needs to
      be carefully prioritized. Oral iron supplement has been widely used and it can be purchased
      over the counter, however, its efficacy is not known in IBD population. Oral iron is poorly
      tolerated with side effects include altered bowel habit, nausea and darken stools, making it
      difficult to adhere to. In contrast, intravenous iron therapy with Venofer® has been shown to
      replenish iron store and improve anaemia quickly. To date, the safety of Venofer® use has
      been supported by its post marketing surveillance. Limitations with intravenous iron
      replacement include the need for medical supervision in the setting of limited healthcare
      resources; the need for patients to take multiple days off work and the cost of Venofer®.
      Currently it is uncertain which method of iron replacement is better. The purpose of this
      study is to compare the efficacy and the cost of oral and intravenous iron replacement in the
      setting of iron deficiency anaemia.
    

Detailed description: 
      1.1 Literature

      Iron deficiency anemia is a common and a major management issue in Inflammatory Bowel disease
      [1-3]. Moreover, no factor has been identified in predicting recurrent iron deficiency anemia
      [4]. Iron deficiency and anemia are well recognized causes of fatigue, poor concentration and
      decreased energy level which impact on one's quality of life and ability to maintain
      employment or managing activities of daily living [2, 5]. Iron deficiency anemia is
      multi-factorial in origin and its causes can be divided into disease or patient origin.
      Disease factors include active blood loss from gastrointestinal mucosal ulceration,
      impairment of iron absorption if disease affects the proximal small bowels or a history of
      extensive small bowel resection. Iron absorption and utilization may also be influenced by
      inflammation inducible production of the hepatic origin peptide hormone called hepcidin [5],
      Interleukin 10 (IL10) [6] and interleukin 6 (IL 6) [7, 8]. Inflammatory cytokines such as
      Tumour Necrosis Factor alpha (TNFa) and IL-6 have been shown to cause anorexia in the animal
      model [9]. The major patient factor is dietary aversion of certain food in order to avoid
      exacerbation of existing symptom [10, 11].

      Iron can be replaced either orally or intravenously. To date five studies directly compare
      oral versus intravenous iron therapy in patients with inflammatory bowel disease. Three of
      the studies suggested intravenous iron was superior [12-14], one suggested oral iron was
      superior [15]and one showed no difference[16]. This confusion is evident by a retrospective
      review of a gastroenterology outpatient clinic's experience in detecting and managing iron
      deficiency anaemia in both IBD and non IBD patients[17]. Furthermore, there are studies
      advocating the concurrent use of Erythropoietin which makes it difficult to draw a definite
      conclusion.

      Studies have shown that iron deficient without anaemia is associated with reduced cognitive
      performance and it is reversible with iron supplementation.(18)19) In combination with other
      non specific symptoms such as fatigue and poor concentration span, many clinicians have been
      treating iron deficiency before anaemia occurs. Moreover, the World Health Organization (WHO)
      estimated the number of iron deficient people to be twice that of diagnosed anaemic people,
      (20) therefore, it is more appropriate to use iron deficiency as the inclusion criterion.
      This is in contrast with most of the clinical trials examining iron replacement therapy use
      iron deficiency anaemia as the inclusion criteria. The approach of stratifying the route of
      iron replacement therapy by the degree of anaemia is logical but not evidence based. This
      study seeks to investigate the efficacy of intravenous iron versus oral iron replacement in
      iron deficient patients.

      Bone marrow biopsy staining for iron store is the gold standard for assessing iron store but
      it is invasive, therefore surrogate serum markers such as ferritin and iron saturation are
      used in clinical practice and they have been shown to be accurate.(21) Low ferritin level is
      associated with high (78%-100%) specificity and low iron saturation has a high sensitivity
      for iron deficiency (59%-88%). (22) Moreover, in anaemic IBD population, low ferritin level
      has >90% specificity for iron deficiency. (23) Given some of the IBD patients will have
      'functional' iron deficiency with elevated ferritin and CRP and a low iron saturation, we
      have decided to use iron saturation <16% and ferritin less than 100ug/L to indicate iron
      deficient state. This cut off is consistent with the laboratory standard for University of
      Alberta Hospital.

      1.2 Oral Iron Therapy

      1.2.1 Oral Iron Adverse Events

      Oral iron replacement is often poorly tolerated as evident by published studies where the
      adverse reaction rate has been reported to be as high as 80% [12], the discontinuation rate
      of up to 25% [16, 18]. Less than half of the patients were able to tolerate the prescribed
      dose of oral iron [14]. Some reports suggested oral iron therapy is associated with worsening
      of IBD disease activity [12], although not consistently [14]. Finally, there is controversy
      regarding whether or not oral iron replacement could exacerbate underlying disease through
      increased oxidative stress [18].

      1.2.2. Oral Iron Efficacy

      Semrin et al have demonstrated oral iron absorption is significantly impaired in the context
      of active Crohn's disease when compared to inactive disease state [7]. In the literature, the
      efficacy of oral iron replacement is often defined by an improvement in haemoglobin level by
      20g/L or more from baseline and it has been reported to be as high as 89% [15]. It is worth
      noting that the baseline haemoglobin in the oral replacement cohort of the study by Gisbert
      et al was significantly higher than the intravenous cohort. When using iron studies as an
      endpoint, only 60% of oral iron treatment group were not iron deficient after 5 months of as
      tolerated dose of oral iron replacement [14].

      1.3 Intravenous Iron Therapy

      1.3.1 Intravenous Iron Adverse Events

      The alternative to oral iron is intravenous iron replacement and its formulation has changed
      over time. Chertow et al reviewed the US FDA intravenous iron adverse event data between
      2001-2003 and confirmed a up to 20 times higher rate of life threatening adverse events with
      the high molecular weight iron dextran than iron sucrose [19]. Iron sucrose (1.4+/- 0.5g) has
      been shown to increase HB by 20g/L and/or normalizing haemoglobin in up to 91% of the cohort
      within 12 weeks of treatment [20]. Studies have shown intravenous iron therapy is better
      tolerated than oral iron, with a lower discontinuation rate [13] and a definite improvement
      in the serum ferritin [16]. Intravenous iron replacement ensures adequate total iron
      replacement because there isn't an issue with compliance and it is independent from
      intestinal absorption. Iron sucrose has been shown to be efficacious when oral iron
      replacement is inadequate or intolerable [20]. The disadvantages of intravenous iron include
      it being time consuming for the patient, much more expensive than the oral formulation and
      the ancillary cost. It is uncertain what the true cost of intravenous iron replacement is
      without factoring in efficacy, compliance and the lack of side effect. Intravenous iron usage
      has been shown to be cost effective in chronic renal failure patients on dialysis who has
      insufficient iron stores on maximum tolerated oral supplements [21].

      1.3.2 Intravenous Iron Efficacy

      There have been five direct comparative oral versus intravenous iron replacement studies. The
      earlier comparative study involved smaller number of subjects, 19 patients, with short
      treatment duration of 2 weeks [12] and 6 weeks [16] and in one study, the baseline entry
      criterion between the two groups were different [15]. Appendix one summarises these studies.

      1.4 Potential Aggravating Effects of Iron Therapy on Inflammatory Bowel Disease.

      The role of oral iron in causing intestinal oxidative stress and subsequently increase the
      risk of colorectal dysplasia is a controversial one. Lund et al used 18 healthy volunteers to
      demonstrate that unabsorbed dietary iron is associated with a 40% increase in stool free
      radicals formation and carcinogens production [22]. The hypothesis that dietary iron can
      serve as a catalyst in the formation of highly reactive radical via the Fenton reaction [23,
      24] and thereby causing cellular damage [25] and contributing to carcinogenesis has been
      demonstrated in animal models [26, 27]. A more recent mice model by Seril et al demonstrated
      the superiority of an intraperitoneal iron supplementation in replenishing splenic iron store
      without an increase in colorectal dysplasia rate compared to mice fed oral iron supplements
      [28]. Interestingly, there are conflicting reports regarding the role of intravenous iron
      replacement and the increase in plasma oxidative stress [12, 29] and the significance of this
      data is unknown. Currently, limited human literature is available addressing this issue.

      HYPOTHESIS:

      Primary:

      There is no difference in the efficacy of iron replacement by oral or intravenous route in
      IBD patients.

      Secondary:

      There is no difference in the tolerability of oral and intravenous iron therapy.

      The route of iron replacement does not impact on the colonic bacterial flora composition, the
      underlying IBD state and the oxidative stress of the colonic mucosa as determined by colonic
      biopsies analyzing for endoplasmic reticulum stress.

      Oral iron replacement therapy is a cheap and efficacious way of replacing iron compare to
      intravenous replacement.

      2 Trial Design

      2.1 Primary Endpoint Change in iron saturation at week 8 post initiation of treatment.

      2.2 Secondary Endpoints

      To describe the change in haemoglobin, ferritin, IBDQ, HBI and partial MAYO score in patients
      before and after iron replacement.

      To describe the changes in the colonic endoplasmic reticulum as an indicator of oxidative
      stress.

      To describe the changes in urinary metabolomics from iron replacement To describe the change
      in the faecal bacteria composition pre and post iron replacement.

      2.3 Study Design/Type

      Open label Randomised Control Trial and observer blinded.

      2.4 Randomization

      Eligible all comers will be randomized into either IV or PO iron therapy in a 1:1 ratio.

      Randomization will be performed externally and hold by EPICORE centre. EPICORE centre will
      maintain the randomization code.

      3.1 Trial Treatment/ Duration

      3.2 Dose determination:-

      Total amount of intravenous iron given is calculated by Ganzoni Equation:

      Iron dose (mg) = body weight (kg) x (ideal Hb - actual Hb) x 0.24 + 15mg/kg of iron depot

      3.3 Iron Sucrose: Administered by IV infusion (dilute 5 mL (equiv. Fe 100 mg) in 100ml of
      NaCl 0.9%). Maximum amount of iron sucrose is 300mg per infusion per week.

      3.4 Oral iron: 200mg equivalent of elemental iron is given twice a day for 3 months.

      3.5 Discontinuation if

        -  withdrawal of consent

        -  Significant adverse event such as hypersensitivity reaction, dyspnoea and myalgia with
           iron sucrose. (see appendix 2)

        -  Recurrent intolerable non hypersensitivity reaction such as fatigue and GI disturbance.

      3.6 Product Accountability Iron tablet pill count will take place during the monthly review.

      3.7 Data Identification Appendix 3: Trial activity Schedule.
    

Intervention name(s): Iron Sucrose.; Iron sucrose
Intervention type(s): Drug; Drug
Intervention description(s): The total dose of iron sucrose given will be individualised by calculating their iron deficit.; 300mg of iron sucrose is given intravenously. Three infusions, each one week apart is given to patients with iron deficiency without anemia. For those patient with anemia, four infusions would be given.
Other intervention name(s): Iron sucrose is been marketed in Canada as Venofer.; Venofer
Intervention MeSH terms: Iron; Ferric Oxide, Saccharated
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Iron deficiency; Inflammatory Bowel Disease; Crohn's Disease; Ulcerative colitis