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Iron Supplementation and Side Effects

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.

Condition or disease Intervention/treatment Phase
Iron Deficiency Anemia Iron Overload Dietary Supplement: Ferrous sulfate Dietary Supplement: Aspiron Other: Placebo Not Applicable

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 Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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: Double (Participant, Investigator)
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.
Primary Purpose: Basic Science
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
Actual Study Start Date : January 8, 2018
Actual Primary Completion Date : April 18, 2018
Actual Study Completion Date : April 18, 2018
Arms and Interventions
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 Name: 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 Name: Starch pill

Outcome Measures
Primary Outcome Measures :
  1. Area under the serum iron curve over 8 hours [ Time Frame: 0,1,2,3,4,6 and 8 hours ]
    Serum iron concentrations (µM) measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).

  2. Area under the NTBI curve over 8 hours [ Time Frame: 0,1,2,3,4,6 and 8 hours ]
    NTBI (µM) concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).

  3. Area under the percent transferrin saturation curve over 8 hours [ Time Frame: 0,1,2,3,4,6 and 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 :
  1. Change in protein carbonyls [ Time Frame: Baseline and 21 days ]
    Change from baseline to 21 days of protein carbonyls (nmol/mL) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.

  2. Change in thiobarbituric acid reactive substances (TBARS) [ Time Frame: Baseline and 21 days ]
    Change from baseline to 21 days of TBARS (µM) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.

  3. Change in hepcidin [ Time Frame: Baseline and 21 days ]
    Change from baseline to 21 days of inflammatory status via hepcidin (ng/mL) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.

  4. Change in C-reactive protein [ Time Frame: Baseline and 21 days ]
    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.

  5. Change in serum ferritin [ Time Frame: Baseline and 21 days ]
    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.

  6. Change in hemoglobin [ Time Frame: Baseline and 21 days ]
    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.

  7. Change in hematocrit [ Time Frame: Baseline and 21 days ]
    Change from baseline to 21 days of iron status through hematocrit (%) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks.

  8. Change in soluble transferrin receptor (sTFR) [ Time Frame: Baseline and 21 days ]
    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.

  9. Change in total iron binding capacity (TIBC) [ Time Frame: Baseline and 21 days ]
    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.

  10. Change in glomerular filtration rate (eGFR) [ Time Frame: Baseline and 21 days ]
    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.

  11. Change in creatinine [ Time Frame: Baseline and 21 days ]
    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.

  12. Change in blood urea nitrogen (BUN) [ Time Frame: Baseline and 21 days ]
    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.

  13. Change in aspartate aminotransferase (AST) [ Time Frame: Baseline and 21 days ]
    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.

  14. Change in alanine aminotransferase (ALT) [ Time Frame: Baseline and 21 days ]
    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.

  15. Gastrointestinal symptoms [ Time Frame: 21 days ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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
Contacts and Locations

Locations
Layout table for location information
United States, Iowa
Iowa State University
Ames, Iowa, United States, 50011
Sponsors and Collaborators
Iowa State University
Investigators
Layout table for investigator information
Principal Investigator: Manju B Reddy, PhD Iowa State University
Tracking Information
First Submitted Date  ICMJE May 3, 2019
First Posted Date  ICMJE July 12, 2019
Last Update Posted Date July 12, 2019
Actual Study Start Date  ICMJE January 8, 2018
Actual Primary Completion Date April 18, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
  • Area under the serum iron curve over 8 hours [ Time Frame: 0,1,2,3,4,6 and 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 [ Time Frame: 0,1,2,3,4,6 and 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 [ Time Frame: 0,1,2,3,4,6 and 8 hours ]
    Percent transferrin (%) saturation concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h).
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
  • Change in protein carbonyls [ Time Frame: Baseline and 21 days ]
    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) [ Time Frame: Baseline and 21 days ]
    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 [ Time Frame: Baseline and 21 days ]
    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 [ Time Frame: Baseline and 21 days ]
    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 [ Time Frame: Baseline and 21 days ]
    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 [ Time Frame: Baseline and 21 days ]
    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 [ Time Frame: Baseline and 21 days ]
    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) [ Time Frame: Baseline and 21 days ]
    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) [ Time Frame: Baseline and 21 days ]
    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) [ Time Frame: Baseline and 21 days ]
    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 [ Time Frame: Baseline and 21 days ]
    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) [ Time Frame: Baseline and 21 days ]
    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) [ Time Frame: Baseline and 21 days ]
    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) [ Time Frame: Baseline and 21 days ]
    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 [ Time Frame: 21 days ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Iron Supplementation and Side Effects
Official Title  ICMJE Assessment of Gastrointestinal Symptoms and Other Side Effects After Three Week Oral Ferrous Sulfate and Iron-enriched Aspergillus Oryzae Supplementation in Young Female Subjects
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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: Double (Participant, Investigator)
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.
Primary Purpose: Basic Science
Condition  ICMJE
  • Iron Deficiency Anemia
  • Iron Overload
Intervention  ICMJE
  • Dietary Supplement: Ferrous sulfate
    65 mg Fe as ferrous sulfate
  • Dietary Supplement: Aspiron
    65 mg Fe as iron-enriched koji culture, called AspironTM
    Other Name: Aspergillus oryzae
  • Other: Placebo
    Contains maltodextrin.
    Other Name: Starch pill
Study Arms  ICMJE
  • 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.
    Intervention: Dietary Supplement: 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.
    Intervention: Dietary Supplement: Aspiron
  • 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.
    Intervention: Other: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 10, 2019)
17
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 18, 2018
Actual Primary Completion Date April 18, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04018300
Other Study ID Numbers  ICMJE SEAS
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Publication in a journal
Responsible Party Dr. Manju B. Reddy, Iowa State University
Study Sponsor  ICMJE Iowa State University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Manju B Reddy, PhD Iowa State University
PRS Account Iowa State University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP