Effect of Intravenous Iron Supplementation on Celiac Disease Remission (IRONCEL) (IRONCEL)

Effect of Intravenous Iron Supplementation on Celiac Disease Remission in Patients With Iron Deficiency and Intestinal Villous Atrophy: a Randomized Trial

The study aims is to evaluate the efficacy of intravenous iron supplementation on celiac disease remission (total intestinal mucosal recovery). This randomized multicenter trial compare the administration of intravenous iron by infusion (Ferinject©: 15 mg/kg in NaCl solution in 30 min) and oral iron in combination; to patients receive only oral iron as standard care. The first benefit with IV Iron supplementation is to correct iron deficiency more rapidly than oral iron alone because of trouble of absorption in case of intestinal villous atrophy.

Celiac disease is an autoimmune-like disorder induced in genetically predisposed individuals by dietary proteins from wheat (gluten). Its frequency reaches 1% in Europe. In celiac patients, gluten induces small intestinal villous atrophy and, as a consequence, malnutrition. Celiac disease treatment relies on a long-life strict gluten-free diet that allows clinical and histological recovery and prevents long-term complications (autoimmune diseases, osteoporosis and malignancies). Remission is attested by total villous recovery on duodenal biopsy performed after one year of gluten free diet. Yet, in adults, systematic follow-up of biopsies for several years after gluten free diet initiation has recently revealed persistent villous atrophy in more than 40 % of cases with an increased risk in older patients (up to 56%). Lack of mucosal healing has been associated with the risk of complications in celiac, notably a risk factor for fractures and lymphoma. It is therefore necessary to define strategies to obtain and accelerate full recovery. Iron deficiency is strongly associated with celiac disease and is generally viewed as a consequence of small intestinal lesions and a symptom of malnutrition. Our preliminary clinical retrospective study showed more frequent iron deficiency anemia in celiac patients with (20/70; 29%) than without (11/88; 12.5%) villous atrophy (p = 0.015; OR: 2.78). Our previous experimental study suggests that iron deficiency may sustain tissue damage and delay mucosal recovery in celiac disease. Indeed the transferrin receptor (CD71) is overexpressed in the gut epithelium in case of iron deficiency and can interact with secretory IgA1 present in large amounts in the intestinal lumen of CD patients. Crosslinking of CD71 by polymeric IgA1 can induce production of inflammatory cytokines. Our working hypothesis is therefore that iron deficiency maintains aberrant expression of CD71 at the gut epithelial surface that sustains intestinal inflammation and epithelial damage. Iron supplementation of celiac patients with villous atrophy and iron deficiency may accelerate mucosal healing, villous recovery and remission.

Upper endoscopy with duodenal biopsy will be performed at most one month before randomization, and one month after the last infusion (experimental group) and between the 12th and the 13h month after randomization (control group). Histological analysis (villous recovery, primary endpoint) will be centrally performed by an expert pathologist blind to the group of treatment.

Experimental group will receive intravenous iron infusion (Ferinject©: 15 mg/kg in NaCl solution IV) at randomization, 2weeks after randomization, 4weeks after randomization, and then every month for a total of one year.

Comparison group will not receive any intravenous treatment. Both experimental and comparison groups will receive an oral iron supplementation (100 mg/day).

Experimental group will receive intravenous iron infusion (Ferinject©: 15 mg/kg in NaCl solution IV) at randomization, 2weeks after randomization, 4weeks after randomization, and then every month for a total of one year. Comparison group will not receive any intravenous treatment. Both experimental and comparison groups will receive an oral iron supplementation (100 mg/day).

The primary endpoint is the proportion of patients with total villous recovery (total remission) on the last duodenal biopsies. 6 formalin and 2 frozen duodenal biopsies will be performed. Intestinal mucosal assessment will be performed by a centralized histological analysis according to the Marsh classification. Readers will be blind to the treatment received.

Proportion of patients with atrophic gastritis at V0 and at V14 biopsies (2 in the antrum, 1 in the angulus and 2 in the fundus)

Proportion of patients with partial recovery of intestinal villous atrophy on the last control duodenal biopsies according to Marsh classification (centralized histological analysis). Six formalin and two frozen duodenal biopsies will be performed.

Proportion of patients correcting iron deficiency. Iron parameters (serum iron level (µmol/L), ferritinemia (µg/L), transferrin saturation index) will be assessed at visit V1, V3, V6, V10, V14; correction of iron deficiency is defined by serum iron level > 20 µg/L and transferrin saturation index ≥0.20.

Proportion of patients correcting anaemia during the 12 months participation. Hemoglobin (Hb) level (g/d) will be measured at visit V1, V3, V6, V10, V14. Correction of anaemia is defined by Hb≥12g/L in woman and Hb≥13g/dL in man.

Evolution of serum levels of liver enzymes (AST, ALT, AP, gGT, Total Bilirubin), glycemia, T4, TSH measured at visit V1, V3, V6, V10, V14.

Observance of gluten free diet will be assessed by (i) dietitian assessment of gluten free consumption (g/day and proportion of patients in high (0 g/day), medium (0-50 mg/day), low (>50 mg/day) observance), (ii) measurement of serum celiac antibodies (anti-tTG IgA and anti-deamidated gliadin IgG) and (iii) proportion of patients having gluten immunogenic peptides excretion detected in urine at visit V1, V3, V6,V10, V14.

French Celiac disease questionnaire assessed at V1 and V14 about the evolution of the quality of life for the patient.

Inclusion Criteria: Patients free of mental illness, able to sign consent and >18year Celiac disease confirmed by presence of serum celiac antibodies and villous atrophy on intestinal biopsy before starting gluten free diet (GFD) Intestinal villous atrophy on duodenal biopsy (performed within 1 month) showing villous atrophy Patient under GFD or starting GFD with strict compliance Hemoglobin level (Hb) <12g/dL & Hb>8g/dL Well tolerated anemia Iron deficiency defined by: serum iron level < 11 µmol/L, ferritinemia < 20µg/L and/or transferrin saturation index <0.2 Exclusion Criteria: Patient not able to sign, mental illness, pregnancy Complicated celiac disease: intestinal malignancies Severe anemia (Hb <8g/dL) and/or poorly tolerated anemia requiring systematic iron IV supplementation or blood transfusion Serious severe disease having short-term prognostic implication Contraindication to intravenous iron infusion: known drug allergy Pregnant or breastfeeding women Participation in another interventional trial Patients treated by steroids, immunosuppressors or chemotherapy drugs

Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared

Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered. Data sharing must respect the agreements made with funders. Teams wishing obtain IPD must meet the sponsor and PI team to present scientific (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractual agreement. Processing of shared data must comply with European General Data Protection Regulation (GDPR).