Safe and Efficacious Iron for Children in Kenya

Study Overview
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Brief Summary
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This study will determine whether the haemoglobin response to daily home fortification for 30 days with 3mg iron as NaFeEDTA is non-inferior to 12.5 mg iron as encapsulated ferrous fumarate.

Detailed Description
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Background: Fortification of local complementary foods and supplementation with micronutrient powders including iron has been shown to prevent anaemia. Iron can cause complaints (diarrhoea, constipation, etc.) related to oxidative stress in the intestine, however, and at doses conventionally used for daily supplementation, iron can increase rates of malaria and diarrhoea. A lower dose of iron (3mg/day) as NaFEEDTA can reduce these adverse effects whilst having similar or superior efficacy in improving iron status as conventional-dose iron (12.5mg) as ferrous salts. Objective: The primary aim is to compare daily home fortification with 3mg iron as NaFeEDTA versus 12.5 mg iron as encapsulated ferrous fumarate regarding haemoglobin concentration at the end of the 30-day fortification period. Methods: Rural children aged 12-36 months (n=324) will receive albendazole and praziquantel against helminth infections, and preventive chemotherapy against malaria with dihydroartemisinin-piperaquine. They will subsequently be randomised to daily home fortification for 30 days with sachets containing either a) 3 mg iron as NaFeEDTA; b) 12.5 mg iron as encapsulated ferrous fumarate; or c) placebo. Parents or guardians will be instructed to mix the contents of the sachets with solid or semi-solid, ready-prepared foods. Adherence will be assessed by an electronic monitoring and time-recording device in the cap of a dispensing bottle containing the sachets. At the end of the 30-day fortification period, a venous blood sample will be collected to measure indicators of iron status and inflammation. Children who received iron will continue to be followed for a maximum of 120 days after randomisation to estimate the time point when ≥10% of children has developed severe anaemia (haemoglobin concentration <70 g/L).

Official Title
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Comparison of Home Fortification With Two Iron Formulations in Kenyan Children Protected Against Malaria by Artemisinin-based Combination Therapy: a Placebo-controlled Non-inferiority Trial

Conditions
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Anaemia

Intervention / Treatment
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* Dietary Supplement: Low-dose iron as NaFeEDTA
* Dietary Supplement: Conventional dose iron as ferrous salt
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 12-36 months; Residing in the study area; Planning to be in the area for the duration of the intervention and follow-up; Study protocol accepted and informed consent given by at least one parent or guardian Exclusion Criteria: Known or reported allergy to dihydroartemisinin, piperaquine, benzimidazole drugs or praziquantel; A sibling from the same household already randomised to intervention; Severely malnourished (weight-for-height z-score < -3 SD) (for ethical reasons); Presence of fever (axillary temperature ≥ 37.5 ºC) (to avoid inflammation-induced effects on iron status markers); Presence of reported or suspected systemic disorder (e.g. HIV infection, sickle cell disease) (to avoid inflammation-induced effects on iron status markers and to avoid attrition); Missed one or several doses of the 3-day course of dihydroartemisinin-piperaquine (to ensure that participants are protected against malaria for the duration of the iron intervention); No blood sample collected, or blood volume collected < 5 mL; Haemoglobin concentration < 70 g/L (to prevent severe anaemia).

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 36 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low-dose iron as NaFeEDTA<br>Daily point-of-care fortification of (complementary) foods with 3 mg iron as NaFeEDTA. | Dietary Supplement: Low-dose iron as NaFeEDTA<br>* Daily home fortification for 30 days with 3 mg iron as NaFeEDTA, vitamin A (300 RE μg as retinyl palmitate) and 5 mg zinc (as gluconate)<br>|
| Active Comparator: Conventional dose iron as ferrous salt<br>Daily point-of-care fortification of (complementary) foods with 12.5 mg iron as encapsulated ferrous fumarate. | Dietary Supplement: Conventional dose iron as ferrous salt<br>* Daily home fortification for 30 days with 12.5 mg iron as encapsulated ferrous fumarate, vitamin A (300 RE μg as retinyl palmitate) and 5 mg zinc (as gluconate)<br>|
| Placebo Comparator: Placebo<br>Daily point-of-care fortification of (complementary) foods with placebo. | Dietary Supplement: Placebo<br>* Daily home fortification for 30 days with vitamin A (300 RE μg as retinyl palmitate) and 5 mg zinc (as gluconate)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin concentration |  | End of the 30-day fortification period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Iron status | Iron status will be assessed by plasma concentrations of ferritin and soluble transferrin receptor | End of the 30-day fortification period | 
| Serum concentration of non-transferrin bound iron |  | 3 hours after ingesting the first fortificant dose | 
| Faecal calprotectin concentration | Faecal calprotectin concentration is used as an indicator of intestinal inflammation | End of the 30-day fortification period | 
| P. falciparum infection | P. falciparum infection will be defined as the presence of either asexual parasites in blood smears or parasite antigens (either histidine-rich protein-2, or Plasmodium lactate dehydrogenase) in whole blood | End of the 30-day fortification period | 
| Adherence to intervention | Adherence will be defined for each individual as the number of days that the dispensing bottle has been opened during the 30-day intervention period | End of the 30-day fortification period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Iron, Anemia, Sodium Fe(III)-ethylenediaminetetraacetic acid (NaFeEDTA), Ferrous compounds, Child, preschool, Kenya