Treatment of Iron Deficiency Anaemia in Inflammatory Bowel Disease With Ferrous Sulphate
Condition: Ulcerative Colitis; Crohn's Disease
MeSH terms: Crohn Disease; Inflammatory Bowel Diseases; Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Interventional
Phase: Phase 4

Summary: 
      Iron deficiency anaemia is common in inflammatory bowel disease (IBD), affecting at least 20%
      patients at any one time. Hepcidin, a recently described anti-microbial peptide synthesized
      by the liver, is a key regulator of iron homeostasis. It interferes with absorption of iron
      into enterocytes, macrophages and hepatocytes by binding to ferroportin. Hepcidin levels rise
      when total body iron levels rise and protect against iron overload; conversely, in iron
      deficiency, levels are low. Hepcidin levels also rise under the influence of interleukins
      (IL)-6 and -1, a factor likely to contribute to iron deficient erythropoesis in active IBD.
      Whether hepcidin levels predict resistance to oral iron therapy in IBD is unknown, though it
      may impair its immediate oral absorption. Adult IBD patients who are anaemic report quality
      of life and fatigue scores comparable to those seen in malignancy.

      IBD diagnosed in adolescence interferes with growth, education and employment as well as
      psychosocial and sexual development. Not surprisingly, adolescents with IBD have a high
      prevalence of psychological distress, particular depression. Limited historical, and our own
      data suggest that children and adolescents with IBD are more anaemic than adults, and less
      often treated with oral iron. What is not clear is whether the apparent under-utilisation of
      oral iron in paediatric care is because of a perceived lack of benefit or doctors' concerns
      about possible side effects including worsening disease activity.

      To address these questions, the investigators propose a comparative study of 6 weeks of oral
      iron supplementation in adolescents and adults with iron deficiency anaemia in IBD. Patients
      will be given oral iron supplementation. Before and after iron therapy, the investigators
      shall assess haemoglobin concentrations; IBD activity; quality of life (QOL), perceived
      stress, mood and fatigue; iron metabolism, including serum hepcidin.
    

Detailed description: 
      Methods Before and after iron therapy, we assessed haemoglobin concentrations; iron status
      markers; serum hepcidin concentration; IBD activity; iron tolerance; and QOL, perceived
      stress, mood, coping and fatigue using psychometric questionnaires.

      Patients. Patients aged 13 - 18 years were defined as adolescents, and those aged ≥ 19 years
      as adults. Between January 2012 and April 2015, patients with IBD (ulcerative colitis (UC),
      Crohn's disease or IBDU (IBD unclassified) diagnosed by standard clinical, radiological and
      pathological criteria) who within the next month were due to attend the adult, young people's
      and paediatric IBD clinics at Barts and the Royal London Hospitals, Barts Health Trust or the
      paediatric IBD clinic at Chelsea and Westminster NHS Trust, London, UK, were screened for the
      result of their haemoglobin concentration at their previous clinic attendance. Those found to
      be anaemic were sent a letter of explanation about, and invitation to participate in, the
      trial. They were telephoned 1-2 weeks after this letter was sent to them and asked about
      current and previous iron therapy: those apparently eligible (see below) and verbally
      consenting to participate were then seen by a trial doctor or research nurse either at their
      next clinic appointment, or on another mutually convenient occasion. Informed written consent
      from the patients or their parents, as appropriate, was obtained at this meeting, and
      patients who remained eligible on the basis of their iron therapy history and clinical, and
      haematological criteria were enrolled in the trial.

      Definition of iron deficiency anaemia: Anaemia was defined by age and sex-adjusted World
      Health Organisation criteria (males <13.0 g/dl; females and children aged 13 years <12.0
      g/dl) (WHO 2001). For inclusion in the trial, patients had to be both anaemic and have
      transferrin saturation <18%. They also had to report either tolerance of previous course(s)
      of oral iron, or to be naïve to this treatment.

      Exclusion criteria: Patients were excluded if they did not meet the haematological inclusion
      criteria on the admission-to-study blood test ('screening failures'), if they had been given
      oral or intravenous iron within 3 months, or if they had previously been intolerant of oral
      iron. Other exclusion criteria were age <13 years, vitamin B12 or folate deficiency, anaemia
      caused by drugs used to treat IBD, haemoglobinopathy, presence of stoma or ileoanal pouch,
      severely active IBD requiring hospital admission from clinic, severe cardiopulmonary,
      hepatic, renal or other disease, pregnancy, breast-feeding, use of cholestyramine, and
      inability to speak English well enough to complete the consent form or psychometric
      questionnaires.

      Regulatory and funding considerations: The trial was approved by the Southampton National
      Research Ethics Committee (number 10/H504/90 and EUDRACT number 2010-023797-39) and was
      necessarily registered as a Clinical Trial of an Investigational Medical Product (CTIMP) with
      the Medicines and Healthcare Products Regulatory Agency (number 14620/0035/001-0001) and
      ClinTrials.Gov. The trial was sponsored by Barts Health NHS Trust. The trial was kindly
      funded by a grant from Core and British Society for Paediatric Gastroenterology, Hepatology
      and Nutrition.

      Trial protocol and treatment. At enrolment, demographic data including age, sex, disease
      type, education, marital status, smoking habit, weight and height were recorded. Disease
      type, location, behaviour and extent, using Montreal classifications (Silverberg 2005) and
      previous surgeries were noted from medical records. Patients completed six psychometric
      questionnaires to assess mood, fatigue and quality of life (QOL): the Hospital Anxiety and
      Depression Scale (HADS-A and HADS-D)(Zigmond 1983, Bjelland 2002), the recent and general
      Perceived Stress Questionnaires (PSQ-R and PSQ-G) (Levenstein 1993), the Patient Health
      Questionnaire (PHQ-9) (Kroenke 2001), the Coping Inventory for Stressful Situations
      (CISS)(Endler 2000), the Big Five Inventory (BFI) (Ramstedt or one of the John refs - check
      which is right), the Multi-dimension Fatigue Inventory (MFI) (Smets 1995) and the Short
      Inflammatory Bowel Disease Questionnaire (SIBDQ)(Irvine 1996). Symptomatic disease activity
      was assessed using the Harvey-Bradshaw Index (HBI) for patients with Crohn's disease (Harvey
      1998), and Simple Clinical Colitis Activity Index (SCCAI) for those with ulcerative colitis
      (Walmsley 2001). Blood was collected for blood count, including haemoglobin, iron studies and
      hepcidin, and C-reactive protein (CRP); and a stool sample was obtained for faecal
      calprotectin, as an objective measure of disease activity (Kopylov 2014). Patients were given
      6 weeks treatment with 200mg oral ferrous sulphate (Wockhardt Ltd, Ranbaxy Ireland Ltd) twice
      daily.

      After one week, patients were telephoned to assess tolerance to treatment: those intolerant
      of or non-adherent to oral iron were withdrawn from the trial and asked to attend for repeat
      blood tests, questionnaires and faecal calprotectin as end of trial measures. After 6 weeks
      of iron treatment, the above measurements were repeated and adherence assessed by counting of
      returned iron tablets.

      Outcome measures. The primary outcome measure was mean increase in haemoglobin concentration
      in the adolescent and adult groups after 6 weeks of treatment. Secondary outcome measures in
      the two groups were tolerance of oral iron; changes in disease activity (HBI, SCCAI, CRP,
      faecal calprotectin), SIBDQ, HADS-A, HADS-D, PSQ-R, PSQ-G, PHQ-9, CISS, BFI and MFI scores,
      and relation of serum hepcidin at baseline to haemoglobin response to oral iron. The SCCAI
      was used for scoring clinical disease activity in the three adolescent patients with IBDU.

      Assays Haemoglobin, iron studies and routine biochemistry were measured in the haematology
      and biochemistry laboratories at the Royal London and Chelsea and Westminster Hospitals.
      Serum for hepcidin assays was stored at -800 C until assay in duplicate in the University
      Birmingham by mass spectrometry (Ward 2008). The mass spectrometer was calibrated at each
      assay but because it is not serviced annually, the Research & Development Department at Barts
      Health NHS Trust insists on the statement herein that the hepcidin assay did not meet strict
      GCP compliance regulations. Stool samples were stored at -800 C until the end of recruitment:
      they were then extracted and quantified for calprotectin in duplicate by ELISA (ACCUSAY
      Calprotectin, Launch Diagnostics, Ltd, Longfield, UK) in the Clinical Immunology laboratory
      at Royal London Hospital.
    

Intervention name(s): Ferrous sulphate
Intervention type(s): Drug
Intervention description(s): 200mg tablets.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment