Safe and Efficacious Iron for Children in Kenya (SEICK)

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

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.

Study Overview

• Status: Completed
• Conditions: Anaemia
• Intervention / Treatment: Dietary supplement: Low-dose iron as NaFeEDTA; Dietary supplement: Conventional dose iron as ferrous salt; Dietary supplement: Placebo

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 338
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Nyanza Province
    • Maseno, Nyanza Province, Kenya
      • Maseno University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged 12-36 months;
2. Residing in the study area;
3. Planning to be in the area for the duration of the intervention and follow-up;
4. Study protocol accepted and informed consent given by at least one parent or guardian

Exclusion Criteria:

1. Known or reported allergy to dihydroartemisinin, piperaquine, benzimidazole drugs or praziquantel;
2. A sibling from the same household already randomised to intervention;
3. Severely malnourished (weight-for-height z-score < -3 SD) (for ethical reasons);
4. Presence of fever (axillary temperature ≥ 37.5 ºC) (to avoid inflammation-induced effects on iron status markers);
5. 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);
6. 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);
7. No blood sample collected, or blood volume collected < 5 mL;
8. Haemoglobin concentration < 70 g/L (to prevent severe anaemia).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Haemoglobin concentration	At various time points in the post-intervention period, we will sample children without replacement to measure their haemoglobin concentration. Taking into account our wish to restrict phlebotomies during the post-intervention period to a single occasion per child, we will withdraw the child from further study. These measurements should allow us to estimate the time point when ≥10% of children has developed severe anaemia (haemoglobin concentration <70 g/L).	Single measurement between 30 and 100 days after randomisation

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: Maseno University, Maseno, Kenya
• Investigators: Principal Investigator: Hans Verhoef, PhD, London School of Hygiene and Tropical Medicine

Publications and helpful links

General Publications

• Teshome EM, Oriaro VS, Andango PEA, Prentice AM, Verhoef H. Adherence to home fortification with micronutrient powders in Kenyan pre-school children: self-reporting and sachet counts compared to an electronic monitoring device. BMC Public Health. 2018 Feb 1;18(1):205. doi: 10.1186/s12889-018-5097-2.
• Teshome EM, Prentice AM, Demir AY, Andang'o PEA, Verhoef H. Diagnostic utility of zinc protoporphyrin to detect iron deficiency in Kenyan preschool children: a community-based survey. BMC Hematol. 2017 Jul 27;17:11. doi: 10.1186/s12878-017-0082-z. eCollection 2017.
• Teshome EM, Andang'o PEA, Osoti V, Terwel SR, Otieno W, Demir AY, Prentice AM, Verhoef H. Daily home fortification with iron as ferrous fumarate versus NaFeEDTA: a randomised, placebo-controlled, non-inferiority trial in Kenyan children. BMC Med. 2017 Apr 28;15(1):89. doi: 10.1186/s12916-017-0839-z.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: February 25, 2014
• First Submitted That Met QC Criteria: February 25, 2014
• First Posted (Estimate): February 27, 2014

Study Record Updates

• Last Update Posted (Estimate): April 10, 2015
• Last Update Submitted That Met QC Criteria: April 9, 2015
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Anemia; Iron; Kenya; Child, preschool; Sodium Fe(III)-ethylenediaminetetraacetic acid (NaFeEDTA); Ferrous compounds
• Additional Relevant MeSH Terms: Hematologic Diseases; Anemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Trace Elements; Micronutrients; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Iron; Fe(III)-EDTA
• Other Study ID Numbers: LSHTM-2542