Iron Supplementation and Side Effects

Assessment of Gastrointestinal Symptoms and Other Side Effects After Three Week Oral Ferrous Sulfate and Iron-enriched Aspergillus Oryzae Supplementation in Young Female Subjects

The objective of this study is to examine patient-reported gastrointestinal side effects, as well as iron status indicators, inflammatory markers and oxidative stress following administration of ferrous sulfate and iron-enriched Aspergillus oryzae supplementation.

Study Overview

• Status: Completed
• Conditions: Iron Overload; Iron Deficiency Anemia
• Intervention / Treatment: Dietary supplement: Ferrous sulfate; Dietary supplement: Aspiron; Other: Placebo

Detailed Description

Iron deficiency anemia (IDA) afflicts more than 2 billion people globally, making it the most prevalent nutrient disorder, today. Inadequate dietary intake of iron results in consequences like cognitive decline, fatigue, abnormal growth and adverse pregnancy outcomes. These ramifications have associated burdens on economical progression due to decreased market productivity. Inorganic iron supplements like ferrous sulfate (FeSO4) are most commonly used to treat IDA, however known associated side effects occur, decreasing compliancy in individuals. Moreover, inorganic iron salts present a large bolus of iron to the intestinal lumen, resulting in non-transferrin bound iron which leads to systemic inflammation and further exacerbation of chronic diseases. Organic iron compounds have strong potential to be utilized for supplementation, however only under circumstances in which contain high absorbance. Seventeen subjects were randomized in a three-armed, double-blinded crossover design to examine the differences among three treatments (FeSO4, ASP-s and placebo). Outcomes will be to assess acute inflammatory proteins, oxidative stress, iron status indicators, non-transferrin bound iron and gastrointestinal-related side effects.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Ames, Iowa, United States, 50011
      • Iowa State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Age 18-40
• Female
• BMI < 30 kg/m2
• Nonsmoker
• Non pregnant
• Non lactating
• No food allergies to wheat or dairy
• No history of gastrointestinal diseases/disorders
• Willing to discontinue use of vitamin/mineral supplements
• No medications that interfere with iron absorption
• No blood or plasma donations during study period

Exclusion Criteria:

• History of gastrointestinal diseases or disorders
• Donating blood or plasma two weeks prior to study period
• On medications interfering with iron absorption
• Food allergies to wheat or dairy
• Pregnant or lactating
• Smoker
• Anemic (< 120 g/L)
• Ferritin > 40 ug/L

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ferrous sulfate; Subjects will take a 65 mg Fe capsule of ferrous sulfate, once daily for 21 consecutive days. The first treatment capsule will be consumed with a semi-purified meal (egg albumin, sugar, vanilla, maltodextrose and corn oil) and will have blood drawn hours 0, 1, 2, 3, 4, 6 and 8 post consumption. Serum will be used to determine non-transerrin bound iron, serum iron and percent saturation. Throughout the treatment period, subjects are informed to consume the capsule with food and report symptoms in an online questionnaire. Following three weeks treatment, participants return for a blood draw and oxidative stress indicators are measured. A three week washout period with placebo treatment takes place between treatment crossover.	Dietary supplement: Ferrous sulfate; 65 mg Fe as ferrous sulfate
Experimental: Aspiron; AspironTM which is an iron-enriched supplement will follow the same guidelines and protocol as ferrous sulfate arm. Equivalent 65 mg Fe per capsule will be administered to participants.	Dietary supplement: Aspiron; 65 mg Fe as iron-enriched koji culture, called AspironTM; Other Names: Aspergillus oryzae
Placebo Comparator: Placebo; Participants will follow the same description for the other two experimental treatment groups. Capsules will be given to subjects in opaque formation, therefore will be unable to differentiate the iron supplements.	Other: Placebo; Contains maltodextrin.; Other Names: Starch pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the serum iron curve over 8 hours	Serum iron concentrations (µM) measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).	0,1,2,3,4,6 and 8 hours
Area under the NTBI curve over 8 hours	NTBI (µM) concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).	0,1,2,3,4,6 and 8 hours
Area under the percent transferrin saturation curve over 8 hours	Percent transferrin (%) saturation concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).	0,1,2,3,4,6 and 8 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in protein carbonyls	Change from baseline to 21 days of protein carbonyls (nmol/mL) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in thiobarbituric acid reactive substances (TBARS)	Change from baseline to 21 days of TBARS (µM) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in hepcidin	Change from baseline to 21 days of inflammatory status via hepcidin (ng/mL) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in C-reactive protein	Change from baseline to 21 days of inflammatory status via C-reactive protein (mg/L) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in serum ferritin	Change from baseline to 21 days of iron status through serum ferritin (µg/L) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in hemoglobin	Change from baseline to 21 days of iron status through hemoglobin (g/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in hematocrit	Change from baseline to 21 days of iron status through hematocrit (%) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in soluble transferrin receptor (sTFR)	Change from baseline to 21 days of iron status through sTFR (ng/mL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in total iron binding capacity (TIBC)	Change from baseline to 21 days of iron status through TIBC (µg/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in glomerular filtration rate (eGFR)	Change from baseline to 21 days of kidney function through eGFR (mL/min/1.73m2) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in creatinine	Change from baseline to 21 days of kidney function through creatinine (mg/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in blood urea nitrogen (BUN)	Change from baseline to 21 days of kidney function through BUN (mg/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in aspartate aminotransferase (AST)	Change from baseline to 21 days of kidney function through AST (U/L) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Change in alanine aminotransferase (ALT)	Change from baseline to 21 days of kidney function through ALT (U/L) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.	Baseline and 21 days
Gastrointestinal symptoms	Symptoms questionnaire was distributed 3 days/week over 3 weeks/treatment. Total survey per supplemental treatment included 9 surveys. Participants described how the supplement contributed to gastrointestinal distress, such as, constipation, diarrhea, fatigue, abdominal discomfort, nausea, headaches, and heartburn.	21 days

Collaborators and Investigators

• Sponsor: Iowa State University

Publications and helpful links

General Publications

• Bries AE, Wang C, Agbemafle I, Wels B, Reddy MB. Assessment of Acute Serum Iron, Non-Transferrin-Bound Iron, and Gastrointestinal Symptoms with 3-Week Consumption of Iron-Enriched Aspergillus oryzae Compared with Ferrous Sulfate. Curr Dev Nutr. 2019 Nov 7;3(12):nzz127. doi: 10.1093/cdn/nzz127. eCollection 2019 Dec.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2018
• Primary Completion (Actual): April 18, 2018
• Study Completion (Actual): April 18, 2018

Study Registration Dates

• First Submitted: May 3, 2019
• First Submitted That Met QC Criteria: July 10, 2019
• First Posted (Actual): July 12, 2019

Study Record Updates

• Last Update Posted (Actual): July 12, 2019
• Last Update Submitted That Met QC Criteria: July 10, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: ferrous sulfate; non-transferrin bound iron; oral iron supplement; oral iron supplement side effects
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Anemia, Iron-Deficiency; Iron Overload
• Other Study ID Numbers: SEAS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Publication in a journal

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No