Low Dose Once Daily Oral Iron Treatment of Young Children with Nutritional Iron Deficiency Anemia

Background

Iron deficiency anemia (IDA) is prevalent in young children whose diet includes prolonged breast feeding without iron supplementation and/or excessive cow milk consumption.  Oral iron therapy is recommended to correct the anemia and reconstitute iron stores, but few data exist to guide clinical decision-making.  The recommended dosing of elemental iron has been inconsistent in the literature, ranging from 2 to 6 mg/kg/day, given one to three times daily.  To address the paucity of treatment data, the BESTIRON study (Clinicaltrials.gov NCT01904864) was initiated to compare two liquid oral iron agents (ferrous sulfate and NovaFerrum, an iron polysaccharide) using a once daily, low-dose regimen. 

Methods

This study is a single center, double-blinded, randomized controlled superiority trial.  Inclusion criteria include:  age 9 months to 4 years with nutritional IDA by history and laboratory indices (Hgb <10 g/dL, MCV <70 fl, reticulocyte hemoglobin equivalent (Ret He) <25 pg, serum ferritin <15 ng/mL and/or TIBC >425 mg/dL).  Exclusion criteria include:  evidence of blood loss, malabsorption, other cause of anemia, prematurity (gestational age <30 weeks), major co-morbidity, adequate response to prior iron therapy, or previous receipt of intravenous iron. 

Upon enrollment, subjects are randomized 1:1 to either ferrous sulfate (15 mg/mL) or NovaFerrum (15 mg/mL) dosed at 3 mg/kg elemental iron once daily at bedtime.  Follow-up visits occur at 4, 8, and 12 weeks following study initiation.  Definition of complete response at study exit is: Hgb >11 g/dL, MCV >70 fl, Ret He >25 pg, serum ferritin >15 ng/mL, and TIBC <425 mg/dL. The primary outcome, rate of change in hemoglobin concentration over 12 weeks, cannot yet be determined as enrollment is ongoing.  Here we present the overall combined hematologic response to this “minimalist” treatment regimen for subjects who have completed the study to date.

Results

From 9/1/2013 to 8/1/2015, 72 patients (target accrual 80) enrolled in the study.  Sixty-two subjects (56% male) completed it and are included in the analysis.  Median age was 19 months (range 11 – 41 months).  Subjects were predominantly Caucasian/White (Latino) (61%).  Median baseline and week 12 laboratory values are shown in the Table. Thirteen patients received a transfusion for severe symptomatic anemia (median Hgb 3.6 g/dL, range 2.2 – 5.3 g/dL) prior to study entry.  Forty-six of the 62 subjects (74%) completed all 3 study follow-up visits.  Eleven subjects were lost to follow-up or discontinued study participation.  Five others were considered treatment failures at 8 weeks (hemoglobin increment <0.5 g/dL above baseline) and removed from the study.  Of the 46 subjects who completed all study visits, 20 (43%) met the definition of complete resolution (38% of subjects with baseline hemoglobin <8 g/dL compared to 50% among those with baseline hemoglobin >8 g/dL) and received no further iron therapy.

Conclusion

This analysis of children with nutritional IDA receiving a “patient-friendly” regimen of a single daily dose of 3 mg/kg elemental iron for 12 weeks demonstrates a good hematologic response and suggests that higher doses of iron therapy are not necessary to achieve resolution of anemia.  While most subjects achieved a normal hemoglobin concentration, some required continued iron therapy to assure repletion of iron stores. Adverse effects ascribed to oral iron treatment may result in part from prescribing higher or more frequent iron doses, which may contribute to poor adherence and treatment failure. 

We acknowledge Gensavis Pharmaceuticals, LLC for their support of this investigator-initiated study.

Table. Median Laboratory Values at Baseline and Week 12

	Baseline (N=62) Median (Range)	Week 12 (N=46) Median (Range)
Hemoglobin concentration (g/dL)	8.0 (4.4 – 10.6)	11.9 (9.0 – 13.6)
Mean cell volume (fl)	59.9 (47.3 – 69.8)	72.0 (54.7 – 81.9)
Red cell distribution width (%)      Baseline (n=56), Week 12 (n=46)	21.1 (15.5 – 36.5)	18.7 (12.5 – 26.4)
Reticulocyte count (%)      Baseline (n=60), Week 12 (n=45)	1.4 (0.3 – 3.9)	0.9 (0.4 – 1.8)
Reticulocyte hemoglobin equivalent (pg)      Baseline (n=41), Week 12 (n=40)	17.2 (10.6 – 28.4)	29.5 (15.9 – 34.3)
Serum iron (mcg/dL)	20 (9 – 349)	51 (15 – 394)
Serum ferritin (ng/mL)	2.5 (0.5 – 49.2)	11 (2.4 – 46)
Total iron binding capacity (mg/dL)	513 (236 – 636)	394 (287 – 560)