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Clinical Medicine Insights 
 

DOI: https://doi.org/10.52845/CMI/2022-3-3-3  

CMI 03 (03), 330−337 (2022)                                                                                                                                      
ISSN (O) 2694-4626

 

Research Article                                                                    Open Access Journal                                     

                                                                                                                              

Comparison Of The Efficacy And Safety Of Succrosomial Iron And 

Elementar Iron Supplementation To Treat Iron Deficiency And Iron 

Deficiency Anemia In Preschool Children (3-6 Years): Protocol Of A 

Randomized Clinical Trial. 

Katarzyna Kozikowska
1,2

, Wojciech Bartmiński
3
 , Adam J. Sybilski

1,2 

Corresponding Author: Katarzyna Kozikowska 

1
2nd Department of 

Paediatrics, Centre of 

Postgraduate Medical 

Education, Warsaw, Poland 

2
Department of Paediatrics 

and Neonatology, Central 

Clinical Hospital of the 

Ministry of the Interior, 

Warsaw, Poland 

3
Family Medicine Clinic¸ 

Central Clinical Hospital of 

the Ministry of the Interior, 

Warsaw, Poland 

 

 

 

 

 

 

 

 

 

 

 

Abstract 

Children are particularly vulnerable to iron deficiency and its 

consequences. The estimated prevalence of anemia in the world 

population is about 40%. According to WHO, 47% of preschool 

children and 25% of school-age children suffer from iron deficiency 

anemia.  Results of ongoing studies indicate that iron deficiency and 

anemia in children may impair their further development, both 

neurological and motor. The treatment of choice for iron deficiency and 

iron deficiency anemia is prolonged administration of oral iron 

preparations. Iron ions not absorbed from the intestine determine 

frequent adverse effects, which become a reason to abandon therapy 

with the prolongation of supplementation. Our study was designed to 

compare the efficacy of succrosomal and elemental iron 

supplementation in the treatment of iron deficiency and iron deficiency 

anemia in children aged 3-6 years by evaluating iron metabolism 

parameters. We also planned to assess the side effects of the studied 

supplements, the efficacy of the therapy with a single daily dose and the 

analysis of the occurrence and subsidence with the supplementation of 

clinical symptoms of iron deficiency or iron deficiency anemia in 

children aged 3-6 years. This is the single-center randomized 

comparative study. A total of 100 patients were planned to be enrolled 

in the study. Iron supplementation will be administered for 12 weeks. 

The primary aim of the study is to demonstrate that the effect of the 

application of succrosomal iron preparation is not worse than in the 

case of the application of elemental iron. The secondary objectives are 

to evaluate the adverse effects of the compared preparations, the 

efficacy of iron supplementation administered in a single daily dose and 

assess the occurrence and treatment-related resolution of iron deficiency 

symptoms and iron deficiency anemia in the study population.   

Key words: Anemia, iron, iron deficit, children, supplementation  

Copyright : © 2021 The Authors. Published by Medical Editor and 

Educational Research Publishers Ltd. This is an open access article 

under the CC BY-NC-ND license (https://creativecommons.org/lic 

enses/by-nc-nd/4.0/). 

https://creativecommons.org/lic%20enses/by-nc-nd/4.0/
https://creativecommons.org/lic%20enses/by-nc-nd/4.0/


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Introduction

Children are particularly vulnerable to iron 

deficiency and its consequences. A clinically 

latent iron deficit initially develops in deficiency 

conditions, followed by microcytosis with normal 

hemoglobin concentration, and the final stage is 

anemia [1]. The estimated prevalence of anemia in 

the world population is about 40% [2]. Almost 

80% of all cases are iron deficiency anemia [3]. It 

is estimated that 1.224 billion people worldwide 

suffer from it [4]. According to WHO, 47% of 

preschool children and 25% of school-age 

children suffer from iron deficiency anemia [5]. 

Iron requirement during this period is high and 

difficult to cover with diet. Results of ongoing 

studies indicate that iron deficiency and anemia in 

children may impair their further development, 

both neurological and motor [6,7,8]. The 

treatment of choice for iron deficiency and iron 

deficiency anemia is prolonged administration of 

oral iron preparations. The bioavailability of 

commonly used products is limited [9,10]. Iron 

ions not absorbed from the intestine determine 

frequent adverse effects, which become a reason 

to abandon therapy with the prolongation of 

supplementation. Studies conducted on tissue 

models indicate that intestinal absorption of 

succrosomal iron is nearly 3.5 times higher than 

previously used preparations [11]. In studies 

conducted to date, the efficacy of succrosomal 

iron is comparable, with a favorable safety profile. 

Available studies indicate that using a lower dose 

of the preparation allows achieving a similar 

therapeutic effect with fewer reported side effects. 

So far, no studies have been published comparing 

the efficacy of succrosomal iron supplementation 

with elemental iron in children. 

Study design 

Hypotheses posed 

The study was designed to compare the efficacy of 

succrosomal and elemental iron supplementation 

in the treatment of iron deficiency and iron 

deficiency anemia in children aged 3-6 years by 

evaluating iron metabolism parameters. The 

primary objective is to demonstrate that the effect 

of succrosomal iron in the study population is no 

worse than the standard recommended elemental 

iron. 

We also planned to assess the side effects of the 

studied supplements, the efficacy of the therapy 

with a single daily dose and the analysis of the 

occurrence and subsidence with the 

supplementation of clinical symptoms of iron 

deficiency or iron deficiency anemia in children 

aged 3-6 years. 

Material and methods 

Study site and randomization procedure 

The single-center randomized comparative study 

will be conducted at the 2nd Department of 

Pediatrics of the Medical Center for Postgraduate 

Education of the Central Clinical Hospital of the 

Ministry of Internal Affairs and Administration in 

Warsaw. Patients will undergo block 

randomization. The study compares two groups of 

patients: those supplementing with succrosomal 

iron (Group 1, study group) and those receiving 

elemental iron (Group 2, control group). It is 

planned to analyze the response to treatment in 

subgroups: patients diagnosed with isolated iron 

deficiency and iron deficiency anemia.   

Study group  

Sample size  

Anticipating future statistical analysis and patients 

lost to follow-up, a total of 100 patients were 

planned to be enrolled in the study.  

Inclusion criteria  

 Age 3 to 6 years  

 Iron deficiency assessed by hematological 

parameters according to WHO standards  

 Iron deficiency anemia detected by 

hematological markers according to WHO 

standards  

Exclusion criteria  

 Severe anemia (hemoglobin -2 SD from the 

age-standard)  

 Iron deficiency due to probable blood loss  

 Anemia due to other causes, including genetic 

disorders (e.g., thalassemia, hemolytic anemia, 

etc.)  

 Intravenous iron administration or blood 

transfusion within the past three months  

 Current acute infection (time criterion)  



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 History of intestinal malabsorption  

 Coexisting chronic diseases except for asthma 

and allergies  

 Intolerance to orally administered preparations 

regardless of the cause  

 Prematurity with birth age <35 Hbd  

 Low birth weight <2500 g  

 Child from a multifetal pregnancy  

 Obesity (BMI > 90 pc according to WHO 

percentile grid)  

 Iron supplementation (time criterion)  

Randomization and blinding 

The study participants will be randomly assigned 

to one of two groups - a succrosomal iron 

supplement group or an elemental iron supplement 

group. A diagnosis of iron deficiency or iron 

deficiency anemia in a child cannot be left 

untreated, so the placebo control group is waived. 

It is assumed that an even distribution of patients 

diagnosed with iron deficiency and iron deficiency 

anemia is achieved using block randomization 

within the groups. Because of the need to 

calculate the individual dose of treatment, 

blinding will be done only for patients.   

Intervention  

Iron supplementation will be administered for 12 

weeks. Weight-adjusted iron will be administered 

daily in a single daily dose.   

Study design  

Study participants will undergo a systematic 

evaluation. The initial assessment will include a 

physical examination and laboratory tests: 

peripheral blood count, reticulocyte count, serum 

ferritin and iron levels, TIBC, transferrin, 

transferrin saturation, CRP.   

Follow-up evaluation after 4, 8, and 12 weeks was 

scheduled. Each assessment included a physical 

examination and laboratory tests: peripheral blood 

count, reticulocyte count, serum ferritin and iron 

concentration, TIBC, transferrin, transferrin 

saturation, CRP.  

Duration of study  

The planned duration of iron supplementation in 

all patients is 12 weeks. The study is designed to 

end three months after the inclusion of the last 

participant. Shortening the time of observation of 

individual patients could occur in the lack of 

improvement or worsening of hematological 

status during the observation or occurrence of 

adverse events, preventing further participation in 

the study.   

Endpoints of the study  

The primary aim of the study is to demonstrate, 

based on the assessment of the change in 

hematological parameters, that the effect of the 

application of succrosomal iron preparation in the 

population of preschool children with diagnosed 

iron deficiency or iron deficiency anemia is not 

worse than in the case of the application of 

elemental iron.   

The secondary objectives are to evaluate the 

adverse effects of the compared preparations, the 

efficacy of iron supplementation administered in a 

single daily dose and assess the occurrence and 

treatment-related resolution of iron deficiency 

symptoms and iron deficiency anemia in the study 

population.   

Upon completion of the study, the collected data 

will be summarized and statistically analyzed.  

Reporting of adverse reactions  

According to the current WHO definition, an 

adverse reaction is defined as any untoward 

symptom or condition associated with using an 

investigational product in a patient.   

Adverse effects occurring in connection with 

supplementation of the compared iron 

preparations, their frequency and severity, will be 

analyzed based on questionnaire data. Severe and 

health- or life-threatening side effects of therapy 

to participants will be reported according to local 

requirements and practice. 

Dropout  

A subject who develops circumstances that make 

it impossible to continue in the study will be 

dropped from the study. This applies particularly 

to the serious adverse events development, the 

lack of therapy effectiveness, or unsatisfactory 

patient compliance.  

Withdrawal and discontinuation  

You have the right to refuse to participate in the 

study or to withdraw from it at any time. Patients 

who do not complete the study, regardless of the 

reason, will not be included in the statistical 



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analysis. Withdrawal due to adverse reactions to 

therapy is a separate category. All adverse 

reactions observed during the conduct of the study 

will be included in the final analysis, regardless of 

whether or not they affected the conduct of 

supplementation according to the study protocol.   

Discussion  

Iron deficiency is the most common single 

nutritional deficiency worldwide. The most 

common form of anemia is iron deficiency 

anemia, affecting 20% of the population [12]. It 

results from systemic iron deficiency and is its 

final stage [13]. Certain populations are 

particularly vulnerable to iron deficiency and the 

anemia caused by it, including children. The 

prevalence of isolated iron deficiency in children 

is estimated to be 27-48%, depending on the 

country [14-17]. Iron deficiency anemia affects 

approximately 5% of children [16-24], but is 

estimated to be much more common [15,25,26].   

We chose to study a population of children aged 

3-6 years with a diagnosis of iron deficiency or 

iron deficiency anemia because of the high 

prevalence of the condition in this group. In 

addition, the registration indication for 

succrosomal iron includes patients older than three 

years of age.   

To date, there have been no studies comparing the 

efficacy of supplementation of different oral iron 

preparations. Therefore, we intend to compare the 

efficacy of succrosomal iron supplementation with 

the current standard, elemental iron, in the study 

we designed. The use of block randomization will 

allow us to obtain an even distribution of patients 

with iron deficiency and iron deficiency anemia in 

the study groups. Because of the need to calculate 

the individual dose of preparation, blinding will 

only be done on patients.   

In our study, the diagnoses of iron deficiency and 

iron deficiency anemia will be established based 

on WHO criteria. The diagnosis of isolated iron 

deficiency is made based on the measurement of 

plasma ferritin concentration. The values taken as 

the norm vary from author to author. Some 

investigators consider a concentration of <10 ug/l 

as the lower limit of the norm [14,15]. However, 

most analyses take a concentration of <12 ug/l as 

the lower limit of normal [16,22]. Because of this, 

in our work we will qualify iron deficiency as a 

decrease in plasma ferritin concentration below 12 

ug/l. Ferritin belongs to the group of positive 

acute phase proteins - its concentration should be 

analyzed in conjunction with inflammatory 

markers. In our study, as in other authors, the 

presence of inflammation will be excluded by 

measuring the concentration of C-reactive protein 

(CRP).   

Iron deficiency anemia is diagnosed when the 

hemoglobin level is two standard deviations 

below what is considered normal. In children, 

normal hemoglobin concentrations vary according 

to gender and age. In the population of preschool 

children, normal values are identical for both 

sexes.   

According to WHO, in the population of 

preschool children, anemia is diagnosed with a 

hemoglobin concentration <11 g/dl. The sole 

determination of hemoglobin concentration is not 

sensitive and specific enough to diagnose iron 

deficiency anemia. MCV, MCH, MCHC, TIBC 

and ferritin concentration should also be 

determined. On the other hand, according to the 

American Academy of Pediatrics guidelines, a 

complete iron assessment in a given patient should 

include the measurement of hemoglobin, ferritin, 

hemoglobin in reticulocytes (CHr) and soluble 

receptor for transferrin type 1. CHr is considered 

the most decisive and most sensitive marker of 

systemic iron deficiency [8,27]. The parameter 

reflects the pool of iron available to young RBC 

forms in the bone marrow. It is independent of 

inflammation and validated in children, but it is 

unavailable in most laboratories in Polish 

conditions. CHr will not be evaluated in our work, 

but it seems that a surrogate parameter for CHr 

may be MCH, which will be determined in all 

patients [28]. The soluble receptor for transferrin 

type 1 concentration reflects iron deficiency at the 

cellular level. The parameter has only been 

determined in adults, we do not have a range of 

standards, and we will not evaluate it.  

Considering the above, in the planned study we 

will diagnose iron deficiency anemia based on the 

finding of decreased hemoglobin <11 g/l and 

ferritin <12 ug/l (with negative CRP) with 

additional assessment of MCV, MCH, MCHC and 

TIBC.  



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After completion of supplementation of the 

compared iron preparations, based on the analysis 

of the change in hematological exponents in the 

study groups, we expect at least an equal increase 

in hematological exponents. 

Oral iron supplementation is recognized as 

effective and safe management. The current 

regimens are based on administering an 

individually calculated daily dose in two or three 

parts. In isolated iron deficiency the recommended 

dose of elemental iron is 1-2 mg/kg b.w., in 

anemia 4-6 mg/kg b.w. Intestinal absorption of 

iron from most oral preparations is 10-15%. 

Limited absorption forces the administration of 

higher doses to achieve the intended therapeutic 

effect. Unabsorbed iron ions are probably 

responsible for side effects of the therapy 

[29,30,31]. Currently, lower daily doses are 

proposed to be administered at one time [32]. This 

treatment is supposed to be equally effective, with 

a lower risk of side effects and better patient 

compliance. In most patients, the recommended 

duration of therapy sufficient to saturate body iron 

reserves is three months. In iron deficiency, 

systemic reserves are used up first, followed by 

tissue reserves, so that the pool available for 

hematopoiesis remains unchanged for as long as 

possible. With supplementation, normalization of 

hematological parameters occurs rapidly - an 

increase in reticulocytosis can be observed after 7-

10 days and complete normalization of 

hemoglobin concentration after several weeks of 

therapy. The reserve pool, measured by plasma 

ferritin concentration, is rebuilt on average after 

three months, therefore the total time of 

supplementation in our study will be 12 weeks 

with three assessments of iron metabolism 

exponents before the end of supplementation. 

Some patients discontinue supplementation 

prematurely due to side effects. The efficacy of 

such therapy is temporarily limited. On the other 

hand, once the reserve iron pool is replenished, 

iron administration does not benefit the patient 

and may be harmful. Iron supplementation in 

patients without established deficiency may be 

potentially toxic [33, 34]. In our study, the total 

duration of supplementation will be 12 weeks. A 

follow-up evaluation of patients after 4, 8 and 12 

weeks of treatment is planned. A 1 g/dl increase in 

hemoglobin after two weeks of supplementation is 

considered an adequate response to treatment. 

Cyclic evaluation of patients in the project aims to 

trace the dynamics of changes in hematological 

parameters in the study groups and evaluate the 

adverse effects of supplementation.   

We will compare the efficacy of succrosomal iron 

with elemental iron in patients aged 3-6 years with 

diagnosed iron deficiency and iron deficiency 

anemia because of the high prevalence of the 

condition in this group and the limited efficacy of 

therapy with commonly used preparations. The 

too short duration of supplementation is 

responsible for the failure of standard therapy in 

most cases [35]. Side effects of chronically taken 

iron supplements for some patients are the reason 

for premature discontinuation of therapy. The 

results of studies conducted so far with the use of 

succrosomal iron indicate that it is at least as 

effective as the previously used preparations, and 

the side effects are less frequent and less severe 

[36]. Intestinal absorption of most iron 

preparations is 10-15%. Achieving the intended 

therapeutic effect requires administering the 

higher dose of the preparation to the patient, the 

greater the deficit found initially. Iron ions not 

absorbed from the gastrointestinal tract are 

responsible for side effects. It has been shown that 

in contrast to previously used products, 

succrosomal iron is absorbed along the entire 

length of the intestine [36, 37]. Transport of iron 

ions occurs not only via the conventional pathway 

using a protein transporter in the membrane of the 

enterocyte but also via the transcellular and 

intercellular route [38]. When used in the 

succrosomal formulation, encapsulation of iron in 

microcapsules limits the release of iron ions in the 

intestinal lumen and promotes the formulation of 

an additional reserve pool available for increased 

demand within the enterocytes. In patients with 

refractory anemia resulting from chronic kidney 

disease, the use of succrosomal iron was 

comparably effective as repeated intravenous iron 

injections [39]. In patients with anemia secondary 

to malabsorption after bariatric surgery, 

succrosomal iron administration was as effective 

as intravenous iron preparations [40].  

Available data do not indicate the occurrence of 

serious or life-threatening adverse effects after the 

use of oral iron preparations, but their intake is not 

free of side effects. Gastrointestinal symptoms 

such as abdominal pain, vomiting, or constipation 



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are the most common, and tooth discoloration or 

rash may also occur [41]. Iron supplementation 

with succrosomal iron is associated with fewer 

side effects, and they are less severe than previous 

therapies [42]. Serious, life-threatening side 

effects have also not been observed. 

The need for iron supplementation in patients 

diagnosed with iron deficiency remains 

undisputed. Our study is aimed not only to 

evaluate and compare the efficacy and safety of 

supplementation with two iron preparations. We 

would also like to demonstrate the effectiveness of 

therapy with a single daily dose, which will 

certainly improve patient compliance. Analysis of 

questionnaire data concerning possible symptoms 

of iron deficiency or iron deficiency anemia in 

children included in our study will allow us to 

bring closer the clinical manifestation of these 

conditions. 

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MANUSCRIPT CENTRAL                                                                         Katarzyna Kozikowska et al. 

 

 
 

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How to Cite : Kozikowska, K., Bartmiński, 

W., & Sybilski, A. (2022). Comparison of the 

efficacy and safety of succrosomial iron and 

elementar iron supplementation to treat iron 

deficiency and iron deficiency anemia in 

preschool children (3-6 years): protocol of a 

randomized clinical trial. Clinical Medicine 

Insights, 3(3), 330–337. https://doi.org/10.52 

845/ CMI/2022-3-3-3 


