Clinical trial NCT04721964: Evaluation of the Effects of Routine Iron Supplementation in Children on Gastrointestinal Iron Losses
Official title: Evaluation of the Effects of Routine Iron Supplementation in Children on Gastrointestinal Iron Losses.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Iron Deficiency Anemia
Gastro Intestinal Bleeding
Iron-deficiency
Lead sponsor: Swiss Federal Institute of Technology
Sponsor class: OTHER
Collaborators: name: Jomo Kenyatta University of Agriculture and Technology
First posted: 2021-01-25
Enrollment: 24
Sex: ALL
Minimum age (years): 23
Maximum age (years): 29
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective intervention study
Primary purpose: PREVENTION

Brief summary: Iron deficiency anaemia (IDA) is common among infants and young children in sub-Saharan Africa.Oral iron administration is usually recom-mended as cost effective measure to prevent and treat iron deficiency (ID) and IDA during childhood. In Kenya, national nutrition policies for anaemia prevention recommend a daily dose of 3-6 mg ele-mental iron per kg body weight if a child is diagnosed with anaemia.

Using a novel technology, recent research found increased iron losses during iron supplementation. In an explorative analysis of stool samples collected from Gambian toddlers (Speich et al., 2020), an increase in faecal iron losses during iron supplementation was reported. The present study is aiming to analyse a relationship between routine iron supplementation and increased faecal occult blood losses in 24 Kenyan children with anaemia and iron deficiency in a more structured manner.

Secondary objectives of the study are to measure and monitor iron and inflammatory status during the course of the study and to quantify long-term iron absorption and iron losses during a 12-weeks iron supplementation period, in order to put iron balance into relationship to occurring faecal occult blood losses during such an intervention.

Detailed description: Infants and young children in sub-Saharan Africa have high rates of iron deficiency anaemia (IDA), which adversely affects their growth and cognitive development. WHO recommends daily administration of 3 mg elemental iron per kg body weight in form of drops or syrup in 6-23 month-old ID or anaemic infants. In settings where anaemia prevalence in this age group is \>40%, WHO further recommends daily administration of 10-12.5 mg elemental iron for prevention of ID and anaemia. The Kenyan Ministry of Health adopted the WHO strategy to treat IDA in its "Basic Paediatric Protocols" released in 2016, and specified a dose of 3-6 mg elemental Fe per kg body weight and day.

WHO guidelines for anaemia prevention and control in infants aged 6-23 months are based on a systematic review and meta-analysis of randomized controlled trials investigating the effect of daily iron supplementation on health in infants. The review reported a significantly lower risk of iron-deficiency anaemia in infants when supplemented. However, iron supplements and iron-containing micronutrient powders (MNPs) do not always show efficacy; for example, in a recent large intervention trial in Pakistan, there was no significant effect of 12 months of iron supplementation on haemoglobin status.

Among the many potential factors contributing to the limited success of health and nutrition policies in reducing the prevalence of iron deficiency, increased iron losses during iron supplementation have not been considered. In a recent study in Gambian toddlers, a 3.4-fold increase in iron losses was detected, specifically from 0.22 (0.19;0.29) mg/d to 0.75 (0.55;0.87) mg/d, during a 12-week iron intervention with daily consumption of 12 mg iron as ferrous fumarate in MNPs routinely distributed by the United Nations Children's Fund and the World Food Program. Furthermore, the administered iron dose significantly correlated with faecal haemoglobin concentration in the Gambian toddlers. In a recent iron supplementation pilot study in Kenyan toddlers, the investigators measured a significant increase in faecal haemoglobin concentration during iron supplementation. Increased basal iron losses during iron supplementation could also be detected in 10 Swiss women. Several endoscopy studies have suggested iron supplementation may cause irritation/inflammation of the gut mucosa, potentially leading to gastrointestinal blood losses.

To explore a potential relationship between iron supplementation with common iron supplements and increased faecal occult (small traces of blood, not visible in stool) blood losses, this study will measure haemoglobin and porphyrin content in stool samples collected before and throughout a 91-day iron supplementation intervention. Intervention product will be 6 mg iron / kg body weight as ferric ammonium citrate and ferrous fumarate syrup (Ranbaxy Ranferon-12 Syrup, Ranbaxy Laboratories, Gurgaon, India) administered daily. Faecal occult blood losses will also be compared to absolute iron losses determined by the recently developed dilution of stable iron isotopes methodology. The study population will consist of 24 anaemic 2-years old children in Kwale County of southern coastal Kenya. The hypothesis of the investigators is that iron status will improve, but faecal occult blood losses will increase. The data from this project may provide valuable information towards the development of safer and more effective iron supplementation regimens.

Eligibility criteria: Inclusion Criteria:

* Participation in former Fe_HMO_GOS study (JKUAT/IERC No. 301019) or INSPIRE study (JKUAT/IERC No. JKU/2/4/896B).
* Mildly to moderately anaemic defined as 9.0 g/dL ≤ Hb \< 11 g/dL.
* Iron deficiency defined as ZPP \>80μmol/mol.
* Willingness of the caregiver to participate in the study.
* Residence in the study area for the period of the study.
* The informed consent form has been read and signed by the participant's caregiver (or has been read out to the participant's caregiver in case of illiteracy)
* Assessment of good health by professional staff at Msambweni District Hospital.

Exclusion Criteria:

* Hb \<9 g/L or \>11 g/L.
* Zinc ProtoPorphyrin ≤80 μmol/mol.
* Severe underweight (Z-score weight-for-age ≤-3).
* Severe wasting (Z-score weight-for-height ≤-3).
* Antibiotics consumption in the 7 days prior to screening.
* Consumption of iron supplements in the 14 days prior to screening.
* Any severe metabolic, gastrointestinal, kidney or chronic disease such as diabetes, hepatitis, hypertension, cancer or cardiovascular diseases (according to the guardian's statement or medical examination (health booklet)).
* Participants taking part in other studies requiring the drawing of blood or involving medical or physical interventions.

Primary outcomes:
measure: Fecal occult blood concentration
timeFrame: Day 4-7 (baseline)
measure: Fecal occult blood concentration
timeFrame: Day 32-35
measure: Fecal occult blood concentration
timeFrame: Day 60-63
measure: Fecal occult blood concentration
timeFrame: Day 95-98
Secondary outcomes:
measure: Iron status: Hemoglobin (g/dl) (Hb)
timeFrame: Baseline (day 7)
measure: Iron status: Zinc protoporphyrin (µmol/mol) (ZPP)
timeFrame: Baseline (day 7)
measure: Iron status: Soluble Transferrin Receptor (mg/L) (sTfR)
timeFrame: Baseline (day 7)
measure: Iron status: Serum Ferritin (ug/L) (SF)
timeFrame: Baseline (day 7)
measure: Iron status: Serum Hepcidin (nM)
timeFrame: Baseline (day 7)
measure: Iron status: Hemoglobin (g/dl)
timeFrame: Day 35
measure: Iron status: Zinc protoporphyrin (µmol/mol)
timeFrame: Day 35
measure: Iron status: Soluble Transferrin Receptor (mg/L)
timeFrame: Day 35
measure: Iron status: Serum Ferritin (ug/L)
timeFrame: Day 35
measure: Iron status: Serum Hepcidin (nM)
timeFrame: Day 35
measure: Iron status: Hemoglobin (g/dl)
timeFrame: Day 63
measure: Iron status: Zinc protoporphyrin (µmol/mol)
timeFrame: Day 63
measure: Iron status: Soluble Transferrin Receptor (mg/L)
timeFrame: Day 63
measure: Iron status: Serum Ferritin (ug/L)
timeFrame: Day 63
measure: Iron status: Serum Hepcidin (nM)
timeFrame: Day 63
measure: Iron status: Hemoglobin (g/dl)
timeFrame: Day 98
measure: Iron status: Zinc protoporphyrin (µmol/mol)
timeFrame: Day 98
measure: Iron status: Soluble Transferrin Receptor (mg/L)
timeFrame: Day 98
measure: Iron status: Serum Ferritin (ug/L)
timeFrame: Day 98
measure: Iron status: Serum Hepcidin (nM)
timeFrame: Day 98
measure: Inflammation status: alpha Glycoprotein (g/L)
timeFrame: Baseline (day 7)
measure: Inflammation status: C-reactive protein (mg/L)
timeFrame: Baseline (day 7)
measure: Inflammation status: Fatty Acids Binding Protein (ng/ml)
timeFrame: Baseline (day 7)
measure: Inflammation status: C-reactive protein (mg/L)
timeFrame: Day 35
measure: Inflammation status: alpha Glycoprotein (g/L)
timeFrame: Day 35
measure: Inflammation status: Fatty Acids Binding Protein (ng/ml)
timeFrame: Day 35
measure: Inflammation status: C-reactive protein (mg/L)
timeFrame: Day 63
measure: Inflammation status: alpha Glycoprotein (g/L)
timeFrame: Day 63
measure: Inflammation status: Fatty Acids Binding Protein (ng/ml)
timeFrame: Day 63
measure: Inflammation status: C-reactive protein (mg/L)
timeFrame: Day 98
measure: Inflammation status: alpha Glycoprotein (g/L)
timeFrame: Day 98
measure: Inflammation status: Fatty Acids Binding Protein (ng/ml)
timeFrame: Day 98
measure: Red Blood Cells isotopic composition
timeFrame: Baseline (day 7)
measure: Red Blood Cells isotopic composition
timeFrame: Day 35
measure: Red Blood Cells isotopic composition
timeFrame: Day 63
measure: Red Blood Cells isotopic composition
timeFrame: Day 98
measure: Fecal calprotectin concentration
timeFrame: Day 4-7 (baseline)
measure: Fecal calprotectin concentration
timeFrame: Day 32-35
measure: Fecal calprotectin concentration
timeFrame: Day 60-63
measure: Fecal calprotectin concentration
timeFrame: Day 95-98
Other outcomes:
Locations:
city: Mombasa
country: Kenya
facility: Msambweni County Referral Hospital
state: Kwale
Study officials:
affiliation: ETH
name: Nicole U Stoffel, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Speich C, Wegmuller R, Brittenham GM, Zeder C, Cercamondi CI, Buhl D, Prentice AM, Zimmermann MB, Moretti D. Measurement of long-term iron absorption and loss during iron supplementation using a stable isotope of iron (57 Fe). Br J Haematol. 2021 Jan;192(1):179-189. doi: 10.1111/bjh.17039. Epub 2020 Aug 30.