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Iron Supplementation and Side Effects

Primary Purpose

Iron Deficiency Anemia, Iron Overload

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Ferrous sulfate
Aspiron
Placebo
Sponsored by
Iowa State University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Iron Deficiency Anemia focused on measuring ferrous sulfate, non-transferrin bound iron, oral iron supplement, oral iron supplement side effects

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleAccepts Healthy Volunteers

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

Sites / Locations

  • Iowa State University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Ferrous sulfate

Aspiron

Placebo

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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).
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).
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).

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
May 3, 2019
Last Updated
July 10, 2019
Sponsor
Iowa State University
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1. Study Identification

Unique Protocol Identification Number
NCT04018300
Brief Title
Iron Supplementation and Side Effects
Official Title
Assessment of Gastrointestinal Symptoms and Other Side Effects After Three Week Oral Ferrous Sulfate and Iron-enriched Aspergillus Oryzae Supplementation in Young Female Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
January 8, 2018 (Actual)
Primary Completion Date
April 18, 2018 (Actual)
Study Completion Date
April 18, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Iowa State University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Iron Deficiency Anemia, Iron Overload
Keywords
ferrous sulfate, non-transferrin bound iron, oral iron supplement, oral iron supplement side effects

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Model Description
Three armed, cross-over, double blinded design. Fifteen subjects will be randomized to treatment FeSO4, ASP or placebo for two week per treatment. Following each treatment, will be a two week washout period whereby subjects will not consume a supplement. Baseline and final blood draws of each treatment will be collected, in addition to serum collection at 0h, 1h, 2h, 3h, 4h following one dose to determine NTBI concentration curve.
Masking
ParticipantInvestigator
Masking Description
Treatments will be randomized to A or B. Investigators will be blinded to the corresponding treatment, in addition to the subjects being randomized to follow the sequence of supplements as ACB or BCA.
Allocation
Randomized
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ferrous sulfate
Arm Type
Experimental
Arm Description
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.
Arm Title
Aspiron
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Ferrous sulfate
Intervention Description
65 mg Fe as ferrous sulfate
Intervention Type
Dietary Supplement
Intervention Name(s)
Aspiron
Other Intervention Name(s)
Aspergillus oryzae
Intervention Description
65 mg Fe as iron-enriched koji culture, called AspironTM
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Starch pill
Intervention Description
Contains maltodextrin.
Primary Outcome Measure Information:
Title
Area under the serum iron curve over 8 hours
Description
Serum iron concentrations (µM) measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).
Time Frame
0,1,2,3,4,6 and 8 hours
Title
Area under the NTBI curve over 8 hours
Description
NTBI (µM) concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).
Time Frame
0,1,2,3,4,6 and 8 hours
Title
Area under the percent transferrin saturation curve over 8 hours
Description
Percent transferrin (%) saturation concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).
Time Frame
0,1,2,3,4,6 and 8 hours
Secondary Outcome Measure Information:
Title
Change in protein carbonyls
Description
Change from baseline to 21 days of protein carbonyls (nmol/mL) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.
Time Frame
Baseline and 21 days
Title
Change in thiobarbituric acid reactive substances (TBARS)
Description
Change from baseline to 21 days of TBARS (µM) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.
Time Frame
Baseline and 21 days
Title
Change in hepcidin
Description
Change from baseline to 21 days of inflammatory status via hepcidin (ng/mL) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.
Time Frame
Baseline and 21 days
Title
Change in C-reactive protein
Description
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.
Time Frame
Baseline and 21 days
Title
Change in serum ferritin
Description
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.
Time Frame
Baseline and 21 days
Title
Change in hemoglobin
Description
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.
Time Frame
Baseline and 21 days
Title
Change in hematocrit
Description
Change from baseline to 21 days of iron status through hematocrit (%) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.
Time Frame
Baseline and 21 days
Title
Change in soluble transferrin receptor (sTFR)
Description
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.
Time Frame
Baseline and 21 days
Title
Change in total iron binding capacity (TIBC)
Description
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.
Time Frame
Baseline and 21 days
Title
Change in glomerular filtration rate (eGFR)
Description
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.
Time Frame
Baseline and 21 days
Title
Change in creatinine
Description
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.
Time Frame
Baseline and 21 days
Title
Change in blood urea nitrogen (BUN)
Description
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.
Time Frame
Baseline and 21 days
Title
Change in aspartate aminotransferase (AST)
Description
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.
Time Frame
Baseline and 21 days
Title
Change in alanine aminotransferase (ALT)
Description
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.
Time Frame
Baseline and 21 days
Title
Gastrointestinal symptoms
Description
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.
Time Frame
21 days

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Manju B Reddy, PhD
Organizational Affiliation
Iowa State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Iowa State University
City
Ames
State/Province
Iowa
ZIP/Postal Code
50011
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Publication in a journal
Citations:
PubMed Identifier
32154497
Citation
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.
Results Reference
derived

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Iron Supplementation and Side Effects

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