Oral versus intravenous iron in IBD patients with anti-inflammatory therapy

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut
comprising Crohn*s disease (CD) and ulcerative colitis (UC). Of the 17*million
inhabitants in the Netherlands, about 90.000 individuals have been diagnosed
with CD (mean age of 37.7 (SD 15.9) years) and UC (mean age 46.2 (SD 16.8)
years). The incidence rate (39 new individuals per 100*000 every year)
continues to rise, posing an increasing burden on society. The natural history
of the disease is characterized by shorter or longer periods of inflammation
interspersed with periods of remission. In UC the majority of patients have a
mild-moderate course, which is most active at diagnosis and then in varying
periods of remission or mild activity; about 10%-15% of patients experience an
aggressive course, and the cumulative relapse rate in CD is reported as 53%,
85%, and 90% at 1, 5, and 10 years, respectively.
Anemia is the most common systemic complication in patients with IBD, exceeding
by far the frequencies of other extra-intestinal manifestations (e.g.,
rheumatic, dermatologic and ophthalmologic) commonly associated with IBD.
Anemia in IBD is of multifactorial origin; it results from chronic intestinal
blood loss, nutritional deficiencies, medication-induced myelosuppression, and
iron malabsorption due to underlying inflammatory processes. The two most
common types of anemia in IBD are iron-deficiency anemia (IDA), occurring in
45% in all patients with IBD, and anemia of chronic disease (ACD). Multiple
recent studies have shown that iron deficiency anemia (IDA) has a significant
impact on QoL and that iron supplementation can improve QoL, irrespective of
disease activity.

Iron metabolism, including enteral absorption, has been clarified with the
discovery of the master regulator*hepcidin.6 Hepcidin is a peptide hormone;
that is synthesized and produced primarily by the liver. The effect of hepcidin
on iron availability is negative: it reduces iron absorption in the duodenum by
reducing the availability of the iron transporter ferroportin. Reducing the
expression of ferroportin on macrophages and hepatocytes both also reduce the
amount of iron available for production of hemoglobin. In addition, hepcidin
reduces iron release from the reticuloendothelial system (RES).

In a state of iron deficiency, hepcidin is low and ferritin, a marker of bodily
iron stores, is also low and in this state the low hepcidin concentration
facilitates iron absorption. During a state of inflammation, hepcidin can
increase, thereby reducing iron absorption and availability. In ACD the
hepcidin levels are also high, thereby resulting in a low serum iron and high
ferritin levels. The high hepcidin levels that may be present in inflammation
are the reason that iv iron is considered superior to oral iron in patients
with active intestinal inflammation and IDA.

In IBD, successful treatment with either oral or intravenous iron is reflected
by an increase of hemoglobin levels. The European Crohn*s and Colitis
Organization (ECCO) guidelines recommend intravenous iron as a first-line
treatment in patients with active IBD. Oral iron could constitute a valid
alternative for anemia treatment. Side effects of oral iron supplementation
(like nausea, abdominal pain) is the main reason for doctors and patients to
prefer iv iron, especially in patients with active IBD. A 2015 meta-analysis
did not show a dose-dependent effect of GI side effects of oral iron, but on
the other hand, this is not studied properly for patients on daily 100mg iron
(current recommended dose instead of 3 daily 200 mg till recently). A study in
2011 shows long term and low-dose oral iron with no more than 100 mg of total
elemental iron to be equally effective compared with iv iron with a preferable
tolerability and is therefore recommended in the current ECCO guidelines for
patients with inactive disease. In patients with active disease, there are
currently no studies comparing the effects of oral vs iv iron supplementation.

Oral iron supplementation in active disease states is controversial. Hepcidin
levels can be considered as the sum effect of all regulatory processes. Studies
suggested that iron stores and hypoxia reduce hepcidin levels even in an
inflammatory state. This is also reflected by a study which demonstrated low
levels of hepcidin in patients with ferritin levels under 30µg/ml, regardless
of disease activity or type. Furthermore, studies show that immunosuppressive
medication decrease the level of hepcidin. This raises the question: is oral
iron a viable alternative for patients under immunosuppressive treatment for
active IBD?

Regarding the current recommended once daily dosing of oral iron (with probably
less side effects than with a 3 times daily dose), and the decrease of hepcidin
in patients on immunosuppressive medication, we hypothesize that patients with
mild to moderate IBD activity on immunosuppressive medication, show the same
level of Hb increase after 12 weeks after either oral or iv iron
supplementation, while the price of oral iron supplementation is significantly
lower.

The proposed study is a multicenter prospective non-inferiority study. Patients
with inflammatory bowel disease on immunosuppressive medication with iron
deficiency anemia, with increased inflammation parameters, but without an
elevated ferritin (<100 µg/L), will be randomized to a treatment group with
either low dose oral iron or iv iron supplementation. This is the starting
point (baseline) of the study.

Hb analysis will be repeated 4 weeks after start iron supplementation,
according to the Dutch guideline regarding follow-up after iron supplementation
(both iv and oral formulation). In case of iv supplementation, the iv infusion
will be repeated in case of insufficient increase of the Hb.
In case of oral iron supplementation and if the Hb is normal at week 4, the
recommendation is to continue ferrofumaraat during another 8-12 weeks at
reduced doses (every other day). In the current study protocol we advise an
additional 12 weeks of a doses regime of 100 mg every day.
In case of oral supplementation and if the Hb is still too low at week 4, 200
mg every day will be continued until week 12. When a normal Hb is present at
week 12, supplementation at a dose of 100 mg every day will be continued until
week 16. In case there is no increase in Hb at week 12, the patient is a
treatment failure and the treatment decision will be made by the treating
physician.

In conclusion, the total treatment duration is 16 weeks. If a patient develops
IDA again, the treatment protocol starts again. In the current study protocol,
each patient will be followed for these 16 weeks and after these 16 weeks
regular care is resumed.

Visits will be planned in order to perform lab measurements (Hb, ferritine,
transferrin saturation, CRP and fecal calprotectin at baseline, week 4, 12 and
16 weeks). Also patients will be asked for side effects every visit and to fill
in questionnaires at baseline, week 12 and week 16 regarding quality of life,
healthcare use, work productivity and patient preference.
The study coordinator works at the Leiden University Medical Center and in
total 7 collaborating regional and academic hospitals in the Netherlands will
participate in this study. All these centers are member of the ICC Consortium.
The national ICC study coordinator will support the study coordinator with
logistics during the course of the study (0.1 FTE).

Study patients will be treated either with intravenous iron or oral iron. The
brandname of the iv iron is dependent on the hospital policy and the doses will
be according to recommended guidelines (weight of patient, see below). Iv iron
is intramural medication without add-on status and needs infusion at daycare.
Patients randomized in the oral group, will all be prescribed ferrofumaraat 200
mg 1 dd. Both the iv as the oral formulations concerns care that is reimbursed
(iv indirectly via DBC).

The risk for study subjects is negligible because patients do not run
additional risk compared to Standard care. Even outside the
context of the study, patients would have to get their biood samples tested as
part of their IBD-care; in addition, they would
need iron therapy for iron deficiency. Because patients need iron therapy,
there is a risk of side effects or allergic reactions. These
side effects are generally mild and reversible (e.g., constipation, tarry
stool, or abdominal pain). Blood tests for study measurements
will be done at the same time as tests for the Standard care; hence, patients
wiii not have an increased risk related to venipuncture.
During 16 weeks, patients have to get tested four times, which yields an
additional 40mi of blood for each blood withdrawal;
however, the total amount of withdrawn blood volume is negligible and it will
not increase patient's risk. Last but not least, patients will have to fill out
several questionnaires over the course of the study. The questionnaires are
short and not intrusive, it will take about 60 minutes to fill out all study
questionnaires.
It is known that iron deficiency and anemia are frequent and recurrent problems
in patients with IBD. Given that this is a study with a
negligible risk, we think it is justified to perform this study. The results
may lead to personalized iron therapy in patients with IBD.

Since proton-pump inhibitors increase the pH in the stomach and duodenum it can
lead to lower oral iron absorption, given that an acidic environment is
necessary for iron dissociation and absorption. Therefore, patients randomized
to oral ferrous fumarate will be advised to stop using proton-pump inhibitors
during iron therapy or will be advised to switch to other type of antacid
(e.g., H2-antagonists that have been shown to have a smaller effect on iron
absorption and association with iron deficiency compared with proton-pump
inhibitors) during iron therapy. Patients randomized to intravenous iron group
can continue using proton-pump inhibitors.