Malaria and the Safety of Iron Supplements and Iron Fortification

Iron Deficiency Clinical Trial

— MIA  

Official title:

Malaria and Iron Intervention Safety: Absorption and NTBI

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01156896
• Other study ID #: AAAF0995
• Secondary ID: U01HD061233-04
• Status: Completed
• Phase: N/A
• First received: July 2, 2010
• Last updated: February 11, 2015
• Start date: July 2010
• Est. completion date: July 2014

Study information

• Verified date: February 2015
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardSwitzerland: EthikkommissionThailand: Ethical Committee
• Study type: Interventional

Clinical Trial Summary

The primary study hypothesis of the investigators is that administration of an iron supplement between meals at a dose like that used in the Pemba trial (~1 mg Fe/kg) during P. falciparum parasitemia will increase plasma non-transferrin-bound iron. A key subsidiary hypothesis is that iron administered with meals in amounts used in food fortification (~0.1 mg Fe/kg) will not produce plasma non-transferrin-bound iron.

This research will be carried out at the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand. The studies are intended to help understand how giving iron and folic acid to preschool children in Pemba, Zanzibar, Tanzania, (the "Pemba trial") in the doses recommended by the World Health Organization, could have resulted in an increase in hospitalizations and deaths. The investigators will examine the most likely explanation, that the dose of iron supplements used in the Pemba trial produced iron in the blood not bound to the usual carrier for iron (a protein called "transferrin"), that is called "non-transferrin-bound iron", abbreviated as NTBI. In children with malaria, this NTBI might favor the growth of malarial parasites or other causes of infection. At present, no studies have been carried out to see if NTBI is present after giving iron to patients with malaria. Using non-radioactive forms of iron (called "stable isotopes"), the investigators will study iron absorption and NTBI after giving a single dose of iron (like that used in the Pemba trial) one day after treatment for malaria has been started, while patients still have malaria parasites in the blood, and then again two weeks later, after the malaria has been cured. The investigators will study adults admitted to the Hospital for Tropical Diseases in Bangkok, Thailand, with malaria. For reasons of safety, the investigators have chosen to study adults in the hospital rather than children living in an area like Pemba but the results should also apply to children. The outcome of this research will help us design ways of safely giving iron in malarious areas to adults and children to prevent or treat iron deficiency.

Description:

This research will determine the effects of acute infection with Plasmodium falciparum on the absorption, pharmacokinetics and metabolism of iron from iron supplements and other iron preparations in non-immune adults in Thailand. Our project will combine measurements of iron absorption during and after successful treatment of acute uncomplicated falciparum malaria with characterization of the pharmacokinetics of the appearance of plasma nontransferrin-bound iron (NTBI) and measurements of the iron regulatory hormone, hepcidin, and other proteins of iron metabolism. We will examine iron supplements like those used in the Pemba supplementation trial (Sazawal et al., Lancet 2006; 367, 133-143) as well as alternative iron interventions that could minimize or avoid the formation of plasma non-transferrin-bound iron. This research has three specific aims:

1. to characterize the pharmacokinetics of the appearance of non-transferrin bound iron in the systemic circulation after oral administration of an iron supplement or other iron intervention;

2. to determine the effect of acute uncomplicated falciparum malaria on absorption of iron from iron supplements and other iron interventions, using erythrocyte incorporation of stable isotopes of iron;

3. to assess the effects of acute uncomplicated falciparum malaria on iron metabolism by repeated measurements of serum hepcidin, transferrin receptor, ferritin, haptoglobin, and concentrations of pro- (Th-1) and anti- (Th-2) inflammatory cytokines, erythrocyte zinc protoporphyrin, and the complete blood count with absolute reticulocyte count and reticulocyte hemoglobin content (CHr).

These studies of the effects of infection with P. falciparum on iron absorption and metabolism will further our basic understanding of the interaction of iron supplements with malaria and other infections. The results could help guide the choice of optimal means for the prevention and treatment of iron deficiency in regions endemic for malaria. Characterization of the pharmacokinetics of changes in plasma iron produced by administration of conventional iron supplements could lead to the design and development of new formulations of supplemental iron that would maximize iron absorption while minimizing risks associated with non-transferrin-bound plasma iron. Because of the public health importance of assuring iron sufficiency in mothers, our studies are focused on women of childbearing age but the results should be broadly applicable to the optimal means of providing iron to infants and children.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• men or premenopausal woman, 18 to 50 years of age;

• peripheral blood positive for asexual forms of P. falciparum (this criterion not applicable to uninfected healthy control subjects);

• women not pregnant by self-report and not planning pregnancy;

• body weight <65 kg.

Exclusion Criteria:

• presence of severe or complicated malaria as defined by WHO criteria;

• clinical evidence of ill health or a history of chronic disorders;

• treatment for mental illness;

• imprisonment;

• institutionalization.

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Anemia, Iron-Deficiency
• Iron Deficiency

Intervention

Dietary Supplement:
• Ferrous sulfate
Ferrous sulfate, ~1 mg Fe/kg body weight, given as a single dose in the fasting state.
• Ferrous sulfate
Ferrous sulfate, ~1 mg Fe/kg body weight, given as a single dose with a standard Thai rice meal.
• Ferrous sulfate
Ferrous sulfate, ~1 mg Fe/kg body weight, given as a single dose with a standard Thai rice meal with added oil.
• Ferrous sulfate
Ferrous sulfate, ~0.1 mg Fe/kg body weight, given as a single dose with a standard Thai rice meal.

Locations

Country	Name	City	State
Thailand	Hospital for Tropical Diseases, Mahidol University	Bangkok

Sponsors (2)

Lead Sponsor	Collaborator
Columbia University	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma non-transferrin-bound iron (NTBI)	After administration of an iron intervention, plasma non-transferrin-bound iron pharmacokinetics will be determined.	0, 2, 4, 8, 12 and 24 hours	No
Secondary	Erythrocyte 58Fe incorporation	Erythrocyte 58Fe incorporation will be measured using stable-isotope techniques.	Determined 2 weeks after iron intervention	No
Secondary	Fractional 57Fe absorption	Fractional 57Fe absorption will be measured using stable-isotope techniques	Determined 2 weeks after iron intervention	No