Malaria and the Safety of Iron Supplements and Iron Fortification (MIA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Columbia University
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Gary M Brittenham, MD, Columbia University
ClinicalTrials.gov Identifier:
NCT01156896
First received: July 2, 2010
Last updated: February 26, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention
Iron Deficiency
Dietary Supplement: Ferrous sulfate

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Malaria and Iron Intervention Safety: Absorption and NTBI

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • Plasma non-transferrin-bound iron (NTBI) [ Time Frame: 0, 2, 4, 8, 12 and 24 hours ] [ Designated as safety issue: No ]
    After administration of an iron intervention, plasma non-transferrin-bound iron pharmacokinetics will be determined.


Secondary Outcome Measures:
  • Erythrocyte 58Fe incorporation [ Time Frame: Determined 2 weeks after iron intervention ] [ Designated as safety issue: No ]
    Erythrocyte 58Fe incorporation will be measured using stable-isotope techniques.

  • Fractional 57Fe absorption [ Time Frame: Determined 2 weeks after iron intervention ] [ Designated as safety issue: No ]
    Fractional 57Fe absorption will be measured using stable-isotope techniques


Estimated Enrollment: 120
Study Start Date: July 2010
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Iron intervention

All study subjects with malaria and all control subjects will receive an iron intervention (supplement or fortification dose of iron).

Control subjects will be studied on only one occasion.

Study subjects with malaria will receive the same iron intervention two weeks later, after the malarial episode has been successfully treated.

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

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01156896

Contacts
Contact: Srivicha Krudsood, M.D., Ph.D. 0066-2-354-9159 tmsks@mahidol.ac.th

Locations
Thailand
Hospital for Tropical Diseases, Mahidol University Recruiting
Bangkok, Thailand, 10400
Contact: Srivicha Krudsood, M.D., Ph.D.    0066-2-247-1688    tmsks@mahidol.ac.th   
Principal Investigator: Srivicha Krudsood, M.D., Ph.D.         
Sponsors and Collaborators
Columbia University
Investigators
Principal Investigator: Gary M. Brittenham, M.D. Columbia University
  More Information

No publications provided

Responsible Party: Gary M Brittenham, MD, James A Wolff Professor of Pediatrics, Columbia University
ClinicalTrials.gov Identifier: NCT01156896     History of Changes
Other Study ID Numbers: AAAF0995, U01HD061233-01
Study First Received: July 2, 2010
Last Updated: February 26, 2014
Health Authority: United States: Institutional Review Board
Switzerland: Ethikkommission
Thailand: Ethical Committee

Keywords provided by Columbia University:
Non-transferrin-bound iron
Iron stable isotopes
Iron deficiency
Malaria
Iron supplementation
Iron fortification

Additional relevant MeSH terms:
Anemia, Iron-Deficiency
Iron Metabolism Disorders
Malaria
Protozoan Infections
Parasitic Diseases
Anemia, Hypochromic
Anemia
Hematologic Diseases
Metabolic Diseases
Iron
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 24, 2014