EffiCacy and sAfEty of Low doSe orAl iRon for Anaemia in IBD (CAESAR)

March 13, 2024 updated by: Liverpool University Hospitals NHS Foundation Trust

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.

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: STAGE 1

The first stage shall recruit 10 patients and is used to assess the incidence of oral iron related toxicity.

Patients will be prescribed:

• Ferrous fumarate syrup 2.5ml/70mg (22.5mg elemental iron) daily for 8 weeks.

If patients experience toxicity (defined as symptoms not tolerated by the patient), the trial medication would be stopped and IV Iron treatment given.

If toxicity occurs in 2 or more patients where we have to stop treatment, we will continue to recruit 30 patients only to the Ferrous fumarate syrup 2.5ml/70mg (22.5mg elemental iron) daily for 8 weeks. If the toxicity is acceptable and the Hb improves, we will continue to recruit to 22.5mg oral iron/day.

If the toxicity is acceptable but there is no improvement in haemoglobin the next patients will be recruited to stage 2.
Drug: Ferrous fumarate syrup 2.5ml/70mg (22.5mg elemental iron)
Ferrous fumarate syrup 2.5ml/70mg (22.5mg elemental iron) daily for 8 weeks (N=10).
Experimental: STAGE 2

Ten subjects each will then be sequentially assigned to one of the following groups:

  • Ferrous fumarate syrup 5ml/140mg (45mg elemental iron) daily for 8 weeks.
  • Ferrous fumarate syrup 5ml/140mg twice daily (90mg elemental iron) for 8 weeks.

If 2 or more patients experience toxicity at Ferrous fumarate syrup 5ml/140mg (45mg elemental iron) or Ferrous fumarate syrup 5ml/140mg twice daily (90mg elemental iron) we will reduce the dose to the previous level of Ferrous fumarate syrup 2.5ml/70mg (22.5mg elemental iron) and continue to recruit.

30 patients shall be used to estimate the change in haemoglobin between baseline and the final analysis point.

If no dose reduction is required, only the last 20 patients shall be used to assess haemoglobin.

The overall endpoint is the haemoglobin level.
Drug: Ferrous fumarate syrup 2.5ml/70mg(45mg elemental iron)
Ferrous fumarate syrup 5ml/140mg (45mg elemental iron) daily for 8 weeks (N=10).
Drug: Ferrous fumarate syrup 2.5ml/70mg (90mg elemental iron)
Ferrous fumarate syrup 5ml/140mg twice daily (90mg elemental iron) for 8 weeks (N=10).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in haemoglobin concentration from baseline to week 8.
Time Frame: 8 weeks
Measured using serum haemoglobin concentration measured in g/L, taken at week 0 and week 8.
8 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of iron stores at baseline and week 8
Time Frame: 8 weeks
Measured using serum ferritin values measured in ug/L taken at week 0 and week 8.
8 weeks
Assessment of faecal calprotectin at baseline and week 8
Time Frame: 8 weeks
Measures on a continuous numeric scale ranging from 21ug/g to 2099ugug. Values outside these thresholds reported as <20ug/g to >2100ug/g.
8 weeks
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.
Time Frame: 8 weeks
SCCAI measured from 0-19 on a continuous numeric scale.
8 weeks
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.
Time Frame: 8 weeks
HBI measured from 0-28 on a continuous numeric scale.
8 weeks
Assessment of quality of life using the IBD-QUK score at baseline and week 8
Time Frame: 8 weeks
IBD-QUK measured from 0-96 on a continuous numeric scale, then expressed as a percentage from 0-100%.
8 weeks
Assessment of patient global assessment of symptom severity by visual analogue score at baseline and week 8.
Time Frame: 8 weeks
A series of eight questions, each comprising a score. The higher the sum of scores, the more severe the symptom profile. Question one pertains to bowel frequency (total number of stools per week), questions two through eight refer to specific gastrointestinal complaints, the severity of which are scored by placing a marker on a 10cm visual scale - the total length of the line marked denotes the severity score for each question.
8 weeks
Assessment of fatigue at baseline and week 8 using IBD-F fatigue score
Time Frame: 8 weeks
Scored using a series of 35 questions, each scored from 0 to 4. The higher the total score (out of a possible total of 140), the higher the severity of fatigue.
8 weeks
Assessment of possible drug-related side effects: nausea, diarrhoea, mood disturbance, sleep disturbance - will all be assessed at baseline and week 8.
Time Frame: 8 weeks
Measured using a binary outcome (yes/no) measure when asked whether any of the aforementioned symptoms have been experienced by the participant during the study period.
8 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Experimental arm 1: Assessment of faecal metabolome composition at baseline and week 8
Time Frame: 8 weeks
Faecal metabolome will be assessed by analysing the faecal headspace volatile organic compounds using semi-quantitative solid-phase microextraction gas chromatography mass spectrometry. Data will be presented using the relative abundance metrics for the key metabolites identified.
8 weeks
Experimental arm 2: Assessment of faecal microbiota composition at baseline and week 8
Time Frame: 8 weeks
Faecal microbiome will be assessed using high throughput metagenomic sequencing. Data will be presented using relative abundance metrics for the key microbes identified.
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Liverpool University Hospitals NHS Foundation Trust

Investigators

  • Principal Investigator: T Conley, Liverpool University Foundation NHS Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 20, 2023

Primary Completion (Estimated)

October 1, 2024

Study Completion (Estimated)

October 1, 2025

Study Registration Dates

First Submitted

February 14, 2024

First Submitted That Met QC Criteria

March 13, 2024

First Posted (Actual)

March 20, 2024

Study Record Updates

Last Update Posted (Actual)

March 20, 2024

Last Update Submitted That Met QC Criteria

March 13, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 5155

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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