A Pilot Study to Assess the Influence of Dietary Organic Acids on Iron Absorption.
Condition: Iron Deficiency Anaemia
MeSH terms: Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Iron deficiency is the most common micronutrient deficiency in the world today, affecting
      more than 60% of the global population (www.who.int/nut/ida.htm). The two main strategies for
      the prevention and treatment of iron deficiency involve fortification of food with iron, or
      direct supplementation with iron tablets. Simple iron salts (e.g. ferrous sulphate) are well
      absorbed but at supplemental levels (and potentially at lower levels, as used in food
      fortificants) can induce free radical activity resulting in gastrointestinal side effects and
      systematic oxidative stress. As a result, supplementation has poor compliance and improvement
      in iron status is compromised. Ferric salts are less inclined to produce side effects and
      although they are relatively well absorbed at fortification levels in food, they are poorly
      absorbed at the higher supplemental doses. Because certain components of food, such as
      organic acids, can facilitate ferric iron absorption, we now wish to determine whether
      dietary organic acids may similarly enable efficient absorption of supplemental ferric iron
      while preventing the formation of non-transferrin-bound iron (NTBI) which is a proxy for free
      radical activity. Our strategy is to use an iterative process between in vitro and in vivo
      experimentation, aimed at identifying the best choice of organic acid and the optimal ratio
      of iron:organic acid. The study was a cross-over, single-dose comparison against
      standard-of-care therapy (namely ferrous sulphate) in mildly iron deficient anaemic women.
      Both the investigational products and the active comparator were administered as a single
      dose on 2 different occasions, i.e. the investigational products on the first study visit and
      the active comparator 14 days later on the second study visit.
    

Detailed description: 
      The study was a first-in-human iron absorption study of ferric iron oxide-organic acid
      preparations (Fe-OAs). The study design was cross-over, single-dose, single-blinded
      comparison against standard-of-care therapy (namely ferrous sulphate) in mildly iron
      deficient anaemic women. Methyl-cellulose capsules containing single doses of Fe-OAs (60 mg
      elemental iron equivalent) were given to four subjects per test mixture to determine iron
      absorption and bioavailability. The study was initially designed in 2 parts (A and B). Part A
      was an iterative process to determine the best choice of organic acids and the optimal ratio
      of iron to organic acid that allowed efficient iron absorption, while part B was a comparison
      of absorption of the two most promising Fe-OA preparations against the standard-of-care
      therapy (namely ferrous sulphate). Following this iterative-based study we had a candidate
      Fe-OA preparation that showed nearly equivalent bioavailability to ferrous sulphate and we
      decided to stop the study at the end of Part A.

      On day 1 of the study (Part A), the participants were given one methyl-cellulose capsule
      containing one of the Fe-OA preparations to be taken on an empty stomach or with a light
      breakfast consisting of water and 2 slices of white bread with jam. Participants were blinded
      to which test preparation they received. Serial serum iron levels were obtained at baseline
      and then 30, 60, 90, 120, 180, 210 and 240 minutes after ingestion of the iron dosage.
      Fourteen days later the participants returned for the second study visit where they ingested
      one ferrous sulphate tablet with a light breakfast, and the same visit protocol was followed.
      Each subject acted as her own control.

      The bioavailability of iron from the Fe-OA preparations was determined by measuring
      erythrocyte incorporation of labelled iron 14 days following a single oral dose. Each Fe-OA
      preparation was labelled with 2 mg of the stable isotope 58Fe per single dose of the Fe-OA
      material. Ferrous sulphate was used as a reference for oral iron therapy and to determine
      individuals who were non-iron absorbers. Non-iron absorbers were defined as those who had no
      significant net area under the curve (AUC) for serum iron following ferrous sulphate oral
      ingestion (i.e. this was defined as a serum iron increase ≤ 5 μM). The data obtained for
      these individuals were excluded from the final analysis.

      The bioavailability of ferrous sulphate was determined using short-term changes in serum iron
      levels using published algorithms.
    

Intervention name(s): ferrous sulphate; ferric iron oxide-organic acid (Fe-OA)
Intervention type(s): Dietary Supplement; Dietary Supplement
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: iron absorption; bioavailability; anaemia; iron deficiency; ferrous sulphate