Clinical trial NCT06321887: EffiCacy and sAfEty of Low doSe orAl iRon for Anaemia in IBD
Official title: A Pilot Study to Assess the Efficacy and Tolerability of Reduced Dose Oral Iron in the Treatment of Iron Deficiency Anaemia in Inflammatory Bowel Disease Patients.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Inflammatory Bowel Disease
Iron Deficiency Anemia
Lead sponsor: Liverpool University Hospitals NHS Foundation Trust
Sponsor class: OTHER_GOV
First posted: 2024-03-20
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is an adaptive, open label study to compare the efficacy and tolerability of 8 weeks of low dose oral iron, in the treatment of iron deficiency anaemia in patients with inflammatory bowel disease (IBD).
Primary purpose: TREATMENT

Brief summary: Iron deficiency anaemia (IDA) is common in inflammatory bowel disease (IBD). However, although iron is commonly prescribed, the amount of elemental iron needed to achieve clinical efficacy, and the optimal method of supplementation, are under debate. This pilot study aims to investigate the efficacy and safety of low dose and standard dose oral iron preparations for the treatment of IDA in patients with IBD.

Detailed description: BACKGROUND:

Anaemia, particularly iron-deficiency anaemia, is a common complication of inflammatory bowel disease (IBD). The prevalence of anaemia (6-74%) and iron deficiency (36-90%) varies widely among reported studies. The predominant cause of iron deficiency in IBD is intestinal blood loss but other factors such as malabsorption and reduced intake may also play a role. Thus, the need for iron supplementation is an often encountered clinical problem in IBD. Although iron is commonly prescribed, the amount of elemental iron needed to achieve clinical efficacy, and the optimal method of supplementation, are under debate. As intravenous (IV) iron supplementation has become safer, calls for increased utilization have appeared. However, there are significant cost implications to using IV iron. On average, a 1-month supply of oral ferrous sulfate costs $12, in comparison with approximately $600-$700 for a treatment cycle of (IV) iron sucrose, excluding the cost of IV administration.

Overall, the comparative studies of IV vs. oral iron do not demonstrate a significant difference in haemoglobin repletion favouring IV iron therapy. Haemoglobin concentrations were similar at the end of treatment in all studies. A single study suggested a superiority for IV iron with a haemoglobin increase greater than 2 g/dl in 47% of the patients on oral iron compared with 66% on IV iron (P = 0.07). However, this could be accounted for by a high withdrawal rate (24%) in the oral iron group. In the largest comparative study, of 196 subjects, median haemoglobin improved similarly, from 8.7 to 12.3 g/dl in the IV group and from 9.1 to 12.1 g/dl in the ferrous sulfate group (P = 0.70). Thus, intravenous iron appears no more effective than oral iron in repletion of iron status as the rate-limiting step appears to be synthesis of red cells, which is not accelerated by IV iron delivery.

The main reason behind the preference of IV iron over oral iron is based on the concern that oral iron may exacerbate IBD. An often-cited study investigating whether oral iron worsens IBD in comparison with IV iron assessed disease activity in 19 IBD patients, 11 with CD and 8 with UC, randomized to either oral ferrous fumarate or IV iron sucrose over a 14-day period. Although the authors argued that disease activity was worsened by oral iron therapy, their use of numerous unconventional assessments weakens this conclusion. The trial was done as a crossover study with a minimum 6-week washout period, so the previous drug therapy may have affected the results. The number of subjects with IBD was small (N = 19). The authors created a synthesized overall disease activity score by combining UC and CD scales and also reported on subscales within activity indexes to identify significant differences. When the two groups were compared, however, there was no statistically significant difference in the overall synthesized disease activity score.

Another factor associated with intolerance of oral iron may be related to the dose of elemental iron administered. In order to maintain iron balance, adult men need to absorb 1-1.5 mg/d, menstruating women need 1-3 mg/d, and pregnant women need approximately 4-5 mg/d. Based on this, the recommended daily allowance of elemental iron is about 8 mg in adult men and postmenopausal women, 18 mg in premenopausal women, and 27 mg in pregnant women. However, most studies investigating the efficacy of oral iron have used a typical dose of 150-200mg/d of elemental iron, 10-20 fold in excess of the recommended daily allowance. Because of the 20% incidence level of intolerance at these conventional doses of elemental iron, recent studies have investigated the efficacy and side effects associated with low-dose oral iron supplementation. A study in the elderly (age \>80) randomised 90 patients with iron-deficiency anaemia to 15, 50, or 150 mg of daily oral elemental iron over 2 months. All three dosage groups experienced a similar, statistically significant increase in haemoglobin after 2 months. These studies have not been done in IBD.

This pilot study aims to investigate the efficacy and safety of low dose and standard dose oral iron preparations.

HYPOTHESIS:

Low dose oral iron is effective and safe in the treatment of iron deficiency anaemia in inflammatory bowel disease.

Eligibility criteria: Inclusion Criteria:

* Patient is willing to participate in the study and has signed the informed consent.
* Patients aged 18-80 years.
* Patients diagnosed with Crohn's disease or ulcerative colitis diagnosed by conventional clinical, radiological and histological criteria.
* Remission or active disease.
* Haemoglobin level 7-13 g/dL men, 7-12 g/dL women and ferritin \<30, normal B12 and folate (or ferritin \<100 but iron sats \<16 in the presence of inflammation defined as CRP\>5mg/L, faecal calprotectin\>250 microgram/g and presence of endoscopic inflammation).

Exclusion Criteria:

* Patients under 18 or unable to give informed consent.
* Patients with advanced liver disease.
* Patients with advanced renal disease with eGFR\<45ml/min
* Previous intolerance to even low doses of oral iron
* Patients with severe cardiovascular disease defined as previous unstable angina and or previous MI without intervention.
* Participation in other trials in the last 3 months.
* Serious inter-current infection or other clinically important active disease (including renal and hepatic disease) and recently diagnosed gastrointestinal tract cancers
* Pregnant, post-partum (\<3months) or breast feeding females
* Erythropoietin therapy.
* Recent blood transfusion within 30 days.
* Recent iron infusion within 30 days.

Primary outcomes:
measure: Change in haemoglobin concentration from baseline to week 8.
timeFrame: 8 weeks
Secondary outcomes:
measure: Assessment of iron stores at baseline and week 8
timeFrame: 8 weeks
measure: Assessment of faecal calprotectin at baseline and week 8
timeFrame: 8 weeks
measure: Assessment of IBD severity. For ulcerative colitis this will be done using simple colitis clinical activity index (SCCAI). Values calculated at week 0 and week 8.
timeFrame: 8 weeks
measure: Assessment of IBD severity. For Crohn's disease (or IBD-unclassified) the Harvey Bradshaw Index (HBI) will be used. Values calculated at week 0 and week 8.
timeFrame: 8 weeks
measure: Assessment of quality of life using the IBD-QUK score at baseline and week 8
timeFrame: 8 weeks
measure: Assessment of patient global assessment of symptom severity by visual analogue score at baseline and week 8.
timeFrame: 8 weeks
measure: Assessment of fatigue at baseline and week 8 using IBD-F fatigue score
timeFrame: 8 weeks
measure: Assessment of possible drug-related side effects: nausea, diarrhoea, mood disturbance, sleep disturbance - will all be assessed at baseline and week 8.
timeFrame: 8 weeks
Other outcomes:
measure: Experimental arm 1: Assessment of faecal metabolome composition at baseline and week 8
timeFrame: 8 weeks
measure: Experimental arm 2: Assessment of faecal microbiota composition at baseline and week 8
timeFrame: 8 weeks
Locations:
city: Liverpool
country: United Kingdom
facility: Liverpool University Foundation NHS Trust
Study officials:
affiliation: Liverpool University Foundation NHS Trust
name: T Conley
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Erichsen K, Ulvik RJ, Nysaeter G, Johansen J, Ostborg J, Berstad A, Berge RK, Hausken T. Oral ferrous fumarate or intravenous iron sucrose for patients with inflammatory bowel disease. Scand J Gastroenterol. 2005 Sep;40(9):1058-65. doi: 10.1080/00365520510023198.
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